Common and not so Common Melanocytic Lesions in Children and Adolescents

Abstract

The acquired melanocytic nevus is the most common lesion encountered by pediatric pathologists and dermatopathologists in their daily practice. In most cases, there are few difficulties in histopathologic diagnosis. However, it is the acquired melanocytic lesion known as the Spitz nevus, with its intrinsic atypical features which becomes the challenge since it exists along a histopathologic and biologic continuum from the atypical Spitz tumor to spitzoid melanoma. The frustration with some of these spitzoid lesions is that even the “experts” cannot agree as to the differentiation of one from the other even at the level of molecular genetics. Other melanocytic lesions are discussed including the congenital melanocytic nevus with its proliferative nodule(s) and melanoma as the ultimate complication. Although uncommon, cutaneous melanoma in the first 2 decades is emerging as a clinical problem especially in young women in the second decade of life. These are ultraviolet-associated neoplasms whose histopathologic and prognostic features are identical to the adult experience. Considerable progress has been made over the past 15 to 20 years in our understanding of cutaneous melanocytic lesions, but gaps still exist in the important group of spitzoid lesions. It can also be anticipated that more cutaneous melanomas in children will be seen in the future based upon epidemiologic studies.

Keywords

melanocytic nevus congenital melanocytic nevus Spitz nevus atypical Spitz tumor spitzoid melanoma

Cutaneous melanocytic lesions are among the most common indications for a skin biopsy or excision in children to include individuals up to the age of 20 years. In our survey of cutaneous lesions submitted for the pathologic examination from children, approximately one-third were melanocytic proliferations (see Table 1 in nonepithelial tumors and tumor-like lesions of the skin and subcutis); the most common diagnostic group, comprising greater than 90% of melanocytic nevi have features of the common acquired nevus whose initial appearance occurs in the postnatal period, usually in the first few years of life with exposure to ultraviolet light. Our experience with the distribution of melanocytic lesions in children is very similar to that reported by others.^1,2 The other major category of melanocytic nevi is the congenital nevus with its characteristic clinical and pathologic features.^3–5

Table 1.

Types of Melanocytic Lesions in the First 2 Decades of Life (2012–2016).

Type	N (%)
Compound nevus	719 (62)
Dermal nevus	229 (20)
Spitz nevus	103 (9)
Junctional nevus	47 (4)
Blue nevus	22 (2)
Spindle cell nevus	15 (1)
Halo nevus	12 (1)
Atypical spitzoid tumor	7 (1)
Deep penetrating nevus	5 (<1)
Malignant melanoma	5 (<1)
Total	1164 (∼100)

Data are compiled from the files of the Lauren V. Ackerman Laboratory of Surgical Pathology, Washington University Medical Center, St. Louis, Missouri.

The classification of melanocytic lesions in children is essentially no different than the one applied to those which come to clinical attention in adults.⁶ A tabulation of the various melanocytic lesions submitted to our dermatopathology laboratory during the period from 2012 to 2016 from children and adolescents is available in Table 1. Approximately 1% of the compound melanocytic nevi were congenital in type based upon the histologic features.⁵ Not unexpectedly, Spitz nevi were proportionately more common in young individuals than would be expected in adult-aged individuals. Likewise, malignant melanoma (MM) is conspicuous by its extremely low prevalence during this survey period.

Before we embark upon our consideration of the various cutaneous melanocytic lesions in children, it is appropriate to recall that the melanocyte is one of the many differentiated derivatives of the neural crest (NC). The NC cells are sequestered early in embryogenesis as a multipotential line of cells that migrate into various peripheral sites including the skin among other extracutaneous locations as melanocytes.⁷ Anomalies and neoplasms of NC have conceptionally been grouped together as neurocristopathies by Bolande, one of the founders of organized pediatric pathology in the United States.⁸ Melanocytic nevi and melanomas are representative types of neoplastic neurocristopathies whose understanding would be benefited by molecular studies in Bolande’s estimation in anticipation of the many insights which have been gained over the past 2 decades.⁹

Congenital Melanocytic Nevus

Congenital melanocytic nevus (CMN) is by definition a pigmented lesion which is recognized at or soon after birth, and the degree or intensity of pigmentation varies at the time of initial detection since a lesion may come to clinical attention later in childhood or even adulthood. The focus can have circular or ovoid contours and is flat initially, and pigmentary intensity may diminish during the first year.⁶ Approximately 1% to 2% of neonates have a CMN, but one study has reported that almost 25% of newborns have congenital or prenatal nevi;¹⁰ these lesions may be solitary (most cases), multiple, or confluent which in some respects correlates with size: small (<1.5 cm), medium (1.5–19.9 cm), and giant (≥20 cm). The size of a CMN is a projected one at adulthood with the use of multipliers.⁴ The incidence of the giant CMN ranges from 1:20 000 to 50 000 live births.¹¹

Other approaches have been proposed in the clinical evaluation of a CMN. For instance, medium-sized lesions are divisible into M1 (1.5–10 cm) and M2 (>10–20 cm); large into L1 (>20–30 cm) and L2 (>30–40 cm); and giant into G1 (>40–60 cm) and G2 (>60 cm).¹² Magana et al.¹³ have suggested another clinicopathologic approach that is designated type I (a single lesion in a single anatomic site) or type II (multiple lesions surrounding a large or giant CMN). A third approach is based on the anatomic distribution of a giant CMN: bathing trunk, upper back and neck-upper back and neck.¹⁴ Additional features of the CMN include the heterogenous coloration, rugosity, nodularity, and hypertrichosis.¹⁵

The giant CMN has implications beyond a cutaneous proliferation of nevus cells to include neurodevelopmental abnormalities with or without evidence of neurocutaneous melanosis (NCM).^16,17 Those other abnormalities are detectable by magnetic resonance imaging in a majority of children with NCM.¹⁸ Encephalocraniocutaneous lipomatosis, epidermal nevus syndrome, lipoma, neurofibroma, and choroid plexus papilloma are other tumors and conditions which have been reported in association with a giant CMN.^19–21

Several earlier studies have attempted to define the histopathologic features which differentiate a CMN from an acquired melanocytic nevus (AMN).^5,22,23 There are few, if any features, which distinguish a CMN from an AMN in terms of the junctional and upper and mid-dermal pattern of nevus cells except for a less prominent nested pattern of nevus cells in the papillary-upper reticular dermis in the CMN. It has been pointed out that substantial melanocytic atypia may be seen in the junctional population of nevus cells in addition to pagetoid spread in the CMN.²⁴ Extension of nevus cells along the sheath of hair follicles is present in both the CMN and AMN and in the latter lesion, one may qualify an AMN as having “congenital features.”²⁵ However, it is below the level of the hair follicle in the CMN that the nevus cells become a dispersed population of single small cells that infiltrate through the deep reticular dermis and along the septa and into the subcutaneous adipose tissue. Nevus cells of the CMN may infiltrate into the fascia and underlying skeletal muscle in the extreme. Linear rows of individual nevus cells are seen as streaming columns of cells through the dermis. The dermal lymphatics, perineural spaces, and eccrine sweat glands may contain nevus cells. The compound pattern of the CMN transitions to a purely dermal pattern with time as in the AMN in older children.²⁶ On occasion, a lymphocytic infiltrate and nonsurgically related sclerosis may be seen. Some have cast doubt on the ability to differentiate a CMN from an AMN in every case.²⁷ Of course, it is helpful to know whether the pigmented lesion was present at birth, but often that history is not available at the time of microscopic examination, especially in older children.

At one time, the reported incidence of MM arising in the CMN was as high as 40% until it was recognized that the one or more nodules were not malignant at all and came to be known as proliferative nodules (PNs).^28–30 These highly cellular nodules are composed of epithelioid, nevoid, or spindle cells which stand out from the surrounding more monotonous and mitotically inactive nevus cells (Figure 1).^30,31 Proliferative nodules are seen in 3% to 20% of giant CMNs.³² Mitotic figures are present in low numbers, and Ki-67 index is generally 10% of less. There are some examples with higher mitotic rates and Ki-67 index especially in those problematic nodules composed of small cells. Concerns about MM should be diminished in those CMNs with multiple PNs. Superficial or deep localization of a nodule(s) is seen in both PN and melanoma. Melanomas are considerably more mitotically active than the PN, and superficial MMs are often ulcerated.³³ Nguyen et al.²⁹ have demonstrated that the distinction between PN and MM is not straightforward in every case.

Melanoma is the most common malignancy arising in CMN with an estimated incidence of 1% to 2%.^16,33,34 The greatest risk of MM is found in those with a giant CMN and the presence of satellite nodules around the nevus. A comprehensive study by Neuhold et al.³⁵ reported that children who develop MMs in CMN are younger than those with MM in later childhood and adolescents in the absence of CMN. The younger group has a substantially thicker (Breslow) MM than those occurring in older children. Melanomas are more likely to arise in the depths of a CMN in contrast to the conventional, non-CMN melanomas from junctional melanocytes.

Other nonmelanocytic neoplasms arising in a CMN include undifferentiated round cell neoplasms, rhabdomyosarcoma, and liposarcoma.^36,37

Another aspect of the CMN, especially, giant type, is the presence of benign nevus cells in regional lymph nodes.^38,39 These nests are composed of small nevus cells similar to those seen in the CMN. However, we have seen examples in which the distinction from metastatic melanoma was a challenging one. Another morphologic aspect of the giant CMN is the presence of heterologous tissues such as cartilage, adipose tissue, and skeletal muscle as manifestations of the hamartomatous nature of this lesion; the various heterologous tissues are ones known to trace their histogenesis to the NC.⁴⁰

In terms of the molecular genetics of CMN, postzygotic somatic mutations have been found in NRAS and BRAF (Table 2).^41,42 However, one study has reported that only NRAS mutations have been identified in large CMNs whereas small- to medium-sized CMNs have BRAF mutations in 30% of cases and the remainder (70%) have NRAS mutations.⁴³ Yet another study found that BRAF mutations are not present in giant CMN.⁴⁴ There appears to be a correlation between the size of the CMN and NRAS mutation.⁴²

Table 2.

Genetic Landscape of Melanocytic Lesions in Children.

Gene	Congenital Melanocytic Nevus	Common Acquired Nevus	Spitz Nevus	Atypical Spitz Tumor	Spitz-like (Spitzoid Melanoma)
BRAF	5%–15%	∼80%	5%–6%	5%–6%	10% (50%–60%)^a
NRAS	70%–90%	2%–3%	2%–3%	2%–3%	Rare
HRAS	N/A	N/A	10%–20%	15%–16%	Rare
ROS, ALK, NTRK1, RET, ROS1, MET	N/A	N/A	50%–55%	55%–60%	35%–40%
GNAQ	60%–75%	N/A	N/A	N/A	N/A

NCM is found in a subset of children with large CMN whose lesion(s) has a posterior axial distribution involving the neck and/or typical back.^45,46 Approximately 10% to 20% of children with large CMN have NCM as defined by the presence of meningeal melanosis or melanoma in the absence of cutaneous melanoma.⁴⁶ Multiple cutaneous “satellites” or smaller CMNs are present as well. Oncogenic missense mutations in Codon 61 of NRAS have been detected in nevocellular lesions in the clinical setting of NCM and multiple CMNs.⁴⁷ However, Salgado et al.⁴⁸ have reported BRAF mutations in NCM as well as congenital melanomas arising in giant CMN in the setting of NCM. CMN may be another disorder in the pathogenetic category of “mosaic RASopathies” together with epidermal nevus syndrome.^49,50

Acquired Melanocytic Nevus

There are many variables which determine the distribution and number of AMNs in a child. Some of these include pigmentary features of the individual, geographic latitude, low versus high altitude, and family history of MM.^4,6 There is also a correlation with the number of AMNs, sun exposure, and the risk of melanoma. Among white children, the mean nevus count is 15 to 30, and in darker skin children, it is 5 to 10 nevi by the end of the first decade when the greatest accumulation of AMNs occurs.⁵¹ Early onset AMNs are thought to be at greatest risk of developing into MMs.^4,6

The most basic pathologic designation for AMNs is the location in the skin of nevus cells in relation to dermo-epidermal junction with nests of nevus cells only at junction (junctional), those with junctional and dermal nests (compound) (Figure 2), and those with only dermal nests (dermal). Within this straightforward outline, many variations and qualifications exist, such as the morphology of the nevus cells as cells resembling the normal junctional melanocytes or ones which are spindled or rounded with abundant cytoplasm as in the spindle and epithelioid melanocytes. Some lesions are flat or macular in appearance whereas others are raised above the surface as a nodule or polyp where the overlying epidermis can display a variety of patterns. Among the flat AMNs, the junctional nevus cells are in regularly distributed nests and/or as a proliferation of single cells in a lentiginous pattern. Any mitotic activity is typically confined to the junctional nests or the most superficial nests in the papillary dermis. Mitotic activity in a nevus is more likely in a CMN or Spitz nevus in a child than in adults.^52–54 Any mitotic figures which are detected should not be atypical. Deep mitotic figures should be viewed with concern though they may be seen as an isolated finding in a CMN or Spitz nevus. Nuclear pseudoinclusions are seen more commonly in MMs but are present in one-third of CMN and AMN including Spitz nevi in a 40% to 45% of cases.⁵⁵ Nevus cells in the dermis are qualified as demonstrating maturation with depth which may represent cellular senescence; larger melanocytes resembling junctional nevus cells are seen in the papillary dermis and with descent into the reticular dermis, the melanocytes become smaller overall including the nucleus with a more condensed chromatin. Enlarged hyperchromatic nuclei and absence of maturation with depth should alert to the possibility of a MM. Multinucleated nevus cells are seen on occasion, and dermal nevus cells may be accompanied by an eosinophilic background resembling the stroma of a neurofibroma with or without Wagner–Meissner-like corpuscles which is referred to as the so-called neurotization. Adipose tissue may be seen in the midst of dermal melanocytes.

Nevocellular nevi have the capacity for partial or complete spontaneous regression (a shared phenomenon with MM). One expression of regression is an intense lymphocytic infiltrate which may be accompanied by a clinical halo representing a circumferential zone of depigmentation.^56,57 The latter is not always seen clinically in the presence of a brisk lymphocytic response. A dense lymphocytic infiltrate may obscure the presence of the underlying nevus cells or result in the formation of irregular nests among the lymphocytes. Halo nevi occur most commonly in adolescents, and there is a predilection for the trunk.^4,6 Because a nevus has a clinical halo, there is no reason to be especially concerned since most of these lesions are compound melanocytic nevi.⁵⁶

Spontaneous regression occurs across the entire spectrum of nevus cell proliferations from CMN, Spitz nevi to MM.⁵⁸ Cytotoxic T-lymphocytes and natural killer cells (CD56) have been implicated in the process of spontaneous regression.⁵⁹ Pigmented macrophages and fibroplasia of the papillary dermis are the histologic features of spontaneous regression which may be partial or complete. Dense sclerosis with sclerodermoid features and without a halo as a type of spontaneous regression has been reported in the CMN as a rare finding.⁶⁰

Compound melanocytic nevus with “dysplastic” or architecturally disordered features (our preferred designation) is characterized by bridging rete with a nested and lentiginous nevus cell proliferation with or without cytologic atypia in the form of nuclear enlargement and varying degrees of hyperchromatism. Lamellar fibroplasia sharply outlines the rete and a mild lymphocytic infiltrate may be present.^61–63 The previously cited references should be consulted for a thorough discussion of the clinical implications of an AMN with dysplastic or architecturally disordered features.

Special site (site-related) melanocytic nevus is defined as an AMN whose histologic features are seemingly unique, but not exclusive, to one of the following specific anatomic sites: the scalp, genital area, and hand/foot.^3,64 The ear, flexural sites, breast, and lower legs have also been included by some as a special site.

Scalp AMN in children may herald the development of additional scalp lesions and to an increase of nevi elsewhere.⁶⁵ The parietal scalp and vertex are the preferred sites, and these lesions are often greater than 6 mm. Nuclear atypia with enlarged nuclei, fine dusty melanin, irregular dermal nests, and bridging rete are some features of the scalp nevus which overlap with the architecturally disordered compound AMN.^66–68

Genital AMN in children and adolescents has a prevalence of 3.5% with a slight male predominance.⁶⁹ Approximately one-third of these lesions are noted at birth. There is a preference for the penile shaft, scrotum (together 80% of cases in males), and labium majora and minora (together 70% of cases in females).⁶⁹ The microscopic features range from an otherwise typical compound melanocytic nevus to one with atypical features which like the scalp nevus overlap with the architecturally disordered melanocytic nevus. A lentiginous and nested pattern of junctional nevus cells is accompanied by variable nuclear enlargement and atypia.⁷⁰ Pagetoid spread of individual nevus cells through the epidermis may also be seen. These lesions may be especially atypical in the presence of lichen sclerosis et atrophicus in a child.⁷¹ The dermal nests, regardless of the junctional atypia, demonstrate orderly maturation with depth. Some of the more difficult nevocellular lesions in our experience have been biopsies of vulvar nevocellular nevi from older children and adolescents. Melanocytic nevi from the breast have features similar to vulvar nevi.⁷²

Acral melanocytic nevus (AcMN) presents on the palm or sole or the nail matrix. In a study of children from Barcelona, AcMNs were detected in almost 20% of cases.⁷³ In a population of Columbian children, 40% had acral melanocytic lesions.⁷⁴ As many as 30% of the lesions are congenital.⁷⁵ The characteristic histologic pattern of nevocellular proliferation is lentiginous in type with single nevus cells and the occasional junctional nest.⁷⁵ Nuclear atypia is mild in most cases.

Eruptive melanocytic nevi are a clinical phenomenon defined by the “rapid” appearance of multiple AMN mainly on the trunk and extremities in immunosuppressed children or in ones with a bullous dermatosis.^76,77 These lesions have also been reported on the palms and soles.⁷⁸ Other than special site features, there are no indications that these nevi have any particularly enhanced risks for malignant progression.

Spitz nevus and its permutations including atypical Spitz or spitzoid tumor and spitzoid melanoma have become integrated into the lexicon of acquired nevocellular lesions with a shared morphology of rounded, ovoid, and spindle-shaped nevus cells with a compound pattern in most cases or less often a pure dermal or junctional pattern. A review of our cases revealed that approximately 10% of all nevocellular lesions in the first 2 decades of life were examples of “Spitz nevi” (Table 1). Spitz recognized that these were problematic nevocellular lesions, mainly in children, and designated them “juvenile melanomas” as a specific subset of MM.⁷⁹ At some point, the juvenile melanoma of Spitz underwent a less pejorative, eponymic name change to spindle and epithelioid Spitz nevus or simply Spitz nevus.

The archetype of the Spitz nevus in a child is a solitary amelanotic flesh-colored, well-circumscribed papule or nodule, typically measuring 1 cm or less.^4,6,80 The prominent vascularity in the suprapapillary/papillary dermis can convey the clinical impression of a pyogenic granuloma. When pigmentation is present, it is generally modest in degree in contrast to the dense coloration of the spindle cell nevus of Reed.

A review of our experience with Spitz nevi and other spindle cell melanocytic lesions from 1990 to 2017 revealed a total of 756 cases of which 82% were examples of the typical compound Spitz nevus (Table 3). The mean and median ages at diagnosis were 8.6 and 8 years, respectively. Approximately 65% of our cases were in children aged 10 years or younger with the peak age between the ages of 4 and 6 years. This experience is similar to others.⁸¹ There were slightly more females than males (384 females/372 males). The head and neck region was the preferred site in 35% of cases where the cheek, ear, and face accounted for 33%, 20%, and 19% of cases in this region, respectively (Table 4).

Table 3.

Spitz, Spitzoid, and Other Spindle Cell Melanocytic Lesions in First 2 Decades.^a

Type	N (%)
Typical Spitz nevus (compound)	620 (82)
Atypical Spitz nevus or tumor	37 (5)
Combined nevus with Spitz features	35 (5)
Spitzoid melanoma	25 (3)
Dermal Spitz nevus	14 (2)
Pigmented spindle cell nevus (REED)	12 (2)
Junctional Spitz nevus	7 (<1)
Cellular blue nevus	6 (<1)
Total	756 (100)

Compiled from the files of the Lauren V. Ackerman Laboratory of Surgical Pathology, Washington University Medical Center, St. Louis, Missouri, 1990–2017.

Table 4.

Anatomic Distribution of Spitz, Atypical Spitzoid Tumor, and Spitzoid Melanoma.

Type	Spitz Nevus N (%)	Atypical Spitzoid Tumor N (%)	Spitzoid Melanoma N (%)
Head and neck	264 (35)	13 (35)	12 (48)
Upper extremity	193 (26)	11 (30)	8 (32)
Lower extremity	186 (25)	9 (24)	5 (20)
Trunk	102 (13)	4 (11)	–
Perineum (penis-2, scrotum-1, vulva-1)	5 (<1)	–	–
Not stated	6 (<1)	–	–
Total	756 (∼100)	37 (100)	25 (100)

Data are compiled from the files of the Lauren V. Ackerman Laboratory of Surgical Pathology, Washington University Medical Center, St. Louis, Missouri, 1990–2017.

There is a set of histopathologic features that characterize the Spitz nevus, but these may not be equally represented in any one lesion:^80,82,83 (1) a nodule with symmetrical growth; (2) epidermal hyperplasia; (3) superficial vascular ectasias; (4) junctional proliferation of spindled and/or epithelioid nevus cells with clefting and vertically oriented nests (Figure 3); (5) Kamino bodies; (6) nested or confluent spindle cell pattern in dermis with reduction of cell size with depth (the so-called maturation with depth); (7) nuclear enlargement in the absence of nuclear pleomorphism, especially in the dermal component; (8) small single-cell pattern at base of lesion; and (9) mitotic figures, if any, usually confined to junctional and superficial dermal nevus cells and in the absence of atypical mitotic figures.^83–85 The nevus cells may be distributed in the epidermis in a pagetoid pattern or as a dermal lesion with a desmoplastic stroma.^86,87 The latter is differentiated from the desmoplastic nevus.⁸⁸ Lymphocytic inflammation is generally inconspicuous, but the halo reaction is seen on occasion.⁸⁹ When pigmentation is present, it is confined to the junctional and superficial dermal nevus cells. Pigmentation in a Spitz nevus tends to increase with time. Most lesions are well circumscribed and have a wedge-shaped growth pattern to the deep dermis or superficial subcutis.

Atypical Spitz nevus or tumor (ASN/AST) has been discussed thoroughly in the literature with an attempt to differentiate it from the typical Spitz nevus.^84,90,91 These lesions have proven to be difficult on more than one occasion for the “experts” to reach a consensus.^92,93 Even the appropriate clinical management of these lesions is fraught with problems other than complete excision.⁹¹ Any number of studies has applied molecular genetic techniques to more precisely define this group of lesions (Table 5).^94,95 Enlarged pleomorphic nuclei with hyperchromatism in nevus cells which are scattered throughout the dermis and mitotic figures are features which should alert to the likelihood of something other than the typical Spitz nevus. Additional discussion of this important group of lesions can be found in the later section on “borderline melanocytic lesions.”

Table 5.

Molecular Landscape of Spitzoid Melanocytic Lesion and Cutaneous Malignant Melanoma.^a

CGH	Spitz Nevus	Atypical Spitzoid Tumor	Spitzoid Melanoma	Malignant Melanoma
CGH	+11p (20%) +2q (rare)	+6p,+11q −9p,−6q	+6p,+11q −9p	+7q,+7p,+6p,+1q,+20q −9p,−5q,− 11q,−10q
FISH	Polysomies	+6p25 +11q13 −9p21(hetero)—low risk −6q23del—low risk when limited to sentinel lymph node	−9p21(homo)—high risk +6p25 and/or +11q13 —intermediate to high risk	6p23 (MYB), 6p25(RREB1), 11q13 (CCND1), Cep6 (centromere), 8q24 (MYC), 9p21 (CDKN2A)
Additional findings			Kinase fusion: TPM3-NTRK1; Rearrangements involving TPM3, ALK, IL64, BAIAP2L1-BRAF; EML4-BRAF; ARID1B-SNX9; PTPRZ1-NFAM1; TERT promoter—124C>T mutation

CGH, comparative genomic hybridization; FISH, fluorescent in situ hybridization; hetero, heterozygous; homo, homozygous.

Table entries represent a compilation and summary of reported molecular genetic abnormalities across the spectrum of Spitz, spitzoid lesions, and malignant melanoma.

Pigmented spindle cell nevus (PSCN) of Reed is regarded as a distinctive lesion from the pigmented Spitz nevus at least by some.^96,97 Only 1% to 2% of AMN are PSCN in the first 2 decades (Table 1). This deeply pigmented lesion generally presents in older children and adolescents, occurs more commonly in females, and has a predilection for the lower extremity and trunk. A flat, pigmented lesion with sharp borders typically measures 8 mm or less. A symmetrical proliferation of uniform, fusiform cells with dense pigmentation is arranged in round, oval, vertical, or horizontal nests along the dermo-epidermal junction (Figure 4). A superficial dermal component, usually contiguous to junctional nevus cells, may be present, but it can be difficult to judge whether the lesion is purely junctional or compound in type in some cases. Atypia and mitotic figures are not seen, but if so, then it is necessary to consider a spindle cell melanoma (exceeding rare in children). Immunohistochemistry demonstrates patchy positive for S100A6 protein unlike the diffuse staining in the Spitz nevus.^98,99

Deep penetrating nevus (DPN) and plexiform spindle cell nevus are considered together since these lesions, assuming that they are distinct entities, can pose difficulties in differential diagnosis.^100–102 DPN has a single growth pattern—a solid wedge-like dermal proliferation of epithelioid cells and spindle cells in some cases (Figure 5). A plexiform pattern consisting of islands of spindle cells has also been described, but there is overlap with the plexiform spindle cell nevus.¹⁰³ Both DPN and plexiform spindle cell nevus are seen in older children and adolescents in approximately one-third of cases. Cellular blue nevus (CBN) and DPN also have overlapping histologic features and marked atypia, and mitotic activity in the plexiform spindle cell nevus creates substantial difficulties in the separation of the benign from malignant.¹⁰³

Genotypic spindle and epithelioid melanocytic lesions include the HRAS-mutated “spitzoid” nevus, kinase fusion-related spitzoid nevus, and BAP1-associated intradermal tumor (Table 2).¹⁰⁴ The HRAS gene is mutated in approximately 10% to 15% of all Spitz nevi, as well as in those lesions designated as “atypical.”¹⁰⁵ The histologic features of this particular nevocellular lesion is a wedge-shaped, dermal-based lesion with DPN-like features.¹⁰⁶ An infiltrative pattern of spindled nevus cells with relatively low cellularity and marked desmoplasia are features which can be mistaken for MM. The prognosis is favorable for these HRAS-positive lesions.

Kinase fusion spindle and epithelioid melanocytic lesion is characterized by the presence of alterations in ROS1, NTRK1, ALK, BRAF, and RET genes in 17%, 16%, 10%, 5%, and 3% of cases, respectively.¹⁰⁷ One issue is whether these lesions constitute specific subsets since these mutations are present across the entire spectrum of Spitz-like lesions without any predictive prognostic value.

ALK mutation-associated melanocytic lesion generally has a compound pattern, and whose dermal component has plexiform features (Figure 6).¹⁰⁸ Overexpression of ALK is demonstrated by immunohistochemistry; the 2 fusion partners are tropomyosin 3 or dynactin.

BAP1-deficient melanocytic neoplasm is another of the several other tumors which have been characterized as an “atypical Spitz tumor.”^109,110 This nodular epithelioid tumor occurs as either a sporadic- or a syndromic-associated neoplasm in which case there is a germline mutation in BAP1.¹¹¹ Other neoplasms in the BAP1 tumor syndrome include adenocarcinoma of the lung, mesothelioma, uveal melanoma, clear cell renal cell carcinoma, and meningioma. The BAPoma is a dermal-based tumor composed of nevus cells with abundant eosinophilic cytoplasm and sharply defined cell membranes (Figure 7). Multiple lesions develop as a rule in the BAP1 tumor syndrome whereas the sporadic tumors are generally solitary.¹¹¹ It is important to recognize this lesion because of its potential genetic implications.

Dermal-based melanocytic lesions are represented by at least 4 entities: blue nevus, cellular BN, epithelioid BN and dermal melanocytoses.¹¹² BN of the common or Tieche-Jadassohn type was diagnosed in 2% of nevocellular lesions in our survey (Table 1). A symmetrical intensely pigmented lesion arising in acral sites or lower trunk is composed of layered fusiform dendritic melanocytes.¹¹³ Most lesions are no more than 4 to 5 mm in greatest dimension. The BN is often first recognized in childhood and even at birth.¹¹⁴

Cellular blue nevus is uncommon in children but is seen as a pigmented nodule or plaque measuring 1 to 3 cm and typically arising in the scalp or gluteal region.¹¹⁵ The superficial dermal pattern has features of a BN, but the more cellular areas are located in the deep dermis and have a spindle cell appearance (Figure 8). Overall, the lesion is well circumscribed and lacks infiltration. Much of the pigmentation in a CBN is present in melanophages. Other variants of BN and CBN include the atypical CBN, sclerosing/desmoplastic BN, and hypomelanotic/amelanotic BN.¹¹⁶ Both BN and CBN have somatic mutations in the GNAQ gene and do not harbor mutations in the BRAF, NRAS, or c-kit genes as does the common acquired nevus or MM.^117,118 All BNs share in common, intense and diffuse expression of the HMB-45, unlike the common melanocytic nevi that have a gradient of staining for this marker. Epithelioid BN is seen in association with the Carney complex, including cardiac myxomas, psammoma-melanotic schwannoma, and other characteristic pathologic manifestations.¹¹⁹

Combined nevocellular nevus is defined as a lesion with at least 2 distinctive melanocytic patterns; one of the largest series reported that the composite common nevocellular and BN was the most frequent pattern constituting 65% of cases.^120,121 The next most common combination was the common nevocellular and DPN in almost 20% of cases. These lesions are seen throughout life and even as a congenital lesion.¹²² Some combined nevi are accompanied by a nonnevocellular process such as trichoblastoma and smooth muscle hamartoma to warrant consideration whether some of these combined lesions are more hamartomas than neoplasms.^123,124 There is also the question whether the so-called clonal nevus with an epithelioid nodule should be considered a type of combined nevus.^125,126

Pigmented epithelioid melanocytoma (PEM) or “animal-type melanoma” is a lesion which is identical in many aspects to the epithelioid BN of the Carney complex, but a consensus on this point may be lacking.^127,128 This lesion is regarded as a type of BN and is one of the more impressively pigmented melanocytic lesions.^100,114,129 In one study of 9 PEMs, 5 presented in individuals younger than 20 years at diagnosis and the youngest was 4 years.¹²⁸ Melanin bleach is often necessary to appreciate the spindle and epithelioid cell morphology. Mitotic activity is variable but low in most cases. Given the depth of the PEM in its location and the frequency of sentinel lymph node positivity, malignant clinical behavior is modest, but one caveat is whether the diagnostic criteria are uniform for putative PEMs.^129,130

Malignant Melanoma

MM in children and adolescents is the most common primary malignancy of skin in this age-group in contrast with the adult experience where basal cell and squamous cell carcinomas are the most common cutaneous malignancies.¹³¹ Approximately 1% to 2% of all MMs present in the first 2 decades of life, and the incidence has been increasing over time, especially in females aged between 15 and 19 years.^132–136 In adults, most cutaneous MMs are the result of ultraviolet radiation which is true as well for adolescents.^6,137 There are several unique settings for MM in children: congenital/neonatal melanoma to 1 year of age (transplacental spread from the mother, melanoma arising in giant congenital nevocellular nevus with or without NCM, or a de novo melanoma); 1 year of age to puberty (arising in giant congenital nevocellular nevus, sporadic, and genetic disorders).^138,139 Among those children aged 15 years or younger, there is a slight male predominance, but beyond 15 years, almost 60% of cases are found in females. Between 75% and 90% of MMs are diagnosed in children over the age of 12 years with the steepest rise in females over the age of 15 years.^139,140 It is estimated that 450 to 475 new cases of MM are seen each year in the first 2 decades of life in the United States.^141,142

Congenital melanoma is defined as a MM present at birth from the vertical transmission of a maternal MM or the equally rare “de novo” congenital MM.^143–145 In terms of MM arising in giant CMN, there is a bimodal age distribution with the initial larger peak in children younger than 16 years and the second smaller peak in adults.¹⁴⁶ The MMs in CMN arise either in the reticular dermis or in the central nervous system, especially in the setting of NCM where a spectrum of melanocytic tumors are reported.^147–149 The prognosis of MM arising in a giant CMN is thought to be less favorable than the de novo or sporadic MM because the former neoplasm arises in the reticular dermis as a “thick” melanoma, but in adults that does not appear to affect the prognosis.¹⁵⁰ In addition to NRAS mutations, congenital melanomas have numerous chromosomal losses and gains.^144,151

Other than some of the unique circumstances in which MM arises in the prepubertal child, such as the transplacental MM and the deep melanoma in the CMN, the prognosis of the de novo MM in the young child is dependent on Breslow depth and presence or absence of epidermal ulceration.^152,153 It was once thought that prepuberal MMs have a better prognosis, but some of these cases of putative MM are likely Spitz nevi.

Sporadic MM comprises the overwhelming majority of cases in the pediatric age-group. Over 90% of cases are examples of superficial spreading MMs with a preference for the lower extremity and trunk.^133–135 Several institutional and registry studies have documented the incidence, clinical presentation, and outcome of MM in children and adolescents with the conclusion that the disease in older children is similar to the experience in adults.^135,136 A study of fatal or metastasizing melanoma in children revealed that the Breslow thickness was greater in children aged 10 years or younger than older children; this former group is represented in part by those whose MMs arose in CMN, but not exclusively.^35,154

Familial melanoma predisposition accounts for 5% to 10% of MM cases.^155–157 CDKN2A germline mutation is present in 20% to 40% of familial melanomas; the MMs in these individuals are densely pigmented and demonstrate considerable pagetoid spread.¹⁵⁸ Including the BAP1 tumor predisposition syndrome, there are at least 14 other melanoma-associated mutations which predispose to the development of MM.^157,159

Borderline melanocytic lesions have been discussed in part in the preceding sections in reference to the proliferative nodule in CMN and the various mutation-associated Spitz-like lesions. The architecturally disordered (or dysplastic) nevus with its characteristic junctional proliferation of nested and lentiginous nevus cells, bridging of rete and papillary lamellar fibrotic pattern may be associated with cytologic atypia of varying degrees of severity to the extent that a complete excision is recommended in those cases with moderate to severe atypia.¹⁶⁰ It is our experience that the latter lesion is far more common than the morphologic family of the Spitz nevus and the other Spitz-like lesions which dichotomize into “atypical Spitz tumor” and “Spitz-like or spitzoid melanoma” (Figure 9). Another study has highlighted some of the problems which are encountered by the pathologist in the diagnosis of these lesions because of ambiguous diagnostic criteria whose consequences are lack of consensus and uncertainty about appropriate management.⁹³ The latter cited study did not include any Spitz lesions from children. The AST, in contrast to the common Spitz nevus, displays more nuclear atypia, multiple dermal mitoses without abnormal mitoses, and a fascicular pattern.^{84,91,161–163} Asymmetry, lack of circumscription, and extension into the subcutis are other features of AST.

There is considerable experience with sentinel lymph node biopsy (SLNB) in AST.¹⁶⁴ Despite the fact that approximately 40% of SLNBs on average are positive, there is no apparent adverse prognostic significance with a 1% death rate or so. It would be interesting to know the incidence of positive SLNBs in the setting of a typical Spitz nevus, but of course, one could not justify in any sense that procedure especially in a child.

Spitz-like or spitzoid melanoma (SPMM) or alternatively “minimal-deviation melanoma of the Spitzian type” is generally characterized as a larger lesion than the Spitz nevus and more frequently ulcerated.¹⁶⁵ Most SPMMs are reported in individuals younger than 20 years, and there is an apparent predilection for the head and neck, but not in the experience of all since they are also reported on the trunk and lower extremity.^166–168 Parenthetically, the head and neck region is the most common site (33% of all cases) for MMs in children younger than 10 years.¹⁶⁹ It would also appear that most MMs of the head and neck in children are either MM, not otherwise specified, or superficial spreading type.^168,169

Uniform criteria for the pathologic diagnosis of SPMM are difficult to sift from the literature, so that the following are features which we have applied to these cases from our own experience: spindle and/or epithelioid cells with nuclear pleomorphism throughout all levels of the lesion; enlarged nucleoli and often multiple in the pleomorphic nucleus; mitotic figures readily identified and at all levels of the dermis and occasional atypical mitotic figures and extension into the subcutis, especially by a bulging nodule of tumor cells or direct infiltration (Figure 10).

Immunohistochemistry and molecular genetic studies have been brought to bear on the differentiation of the Spitz lesions, one from the other, and from the more common cutaneous MM. However, one should be warned that there have been many studies focused on this conundrum, but in more than one instance, data from these have conflicted or contradicted each other. One immunohistochemical approach is the application of 3 markers, p16, Ki-67, and HMB-45, to demonstrate retention of nuclear p16 (a cell cycle regulating protein as the product of CDKN2A), proliferation antigen expressed in the nucleus during the cell cycle and HMB-45 with a maturational gradient of expression with high staining to low staining with depth in the nevus and loss of the gradient with high expression throughout all levels in MM.¹⁷⁰ In the problematic melanocytic lesion with the differential diagnosis of nevus versus MM, there is loss of p16 staining, higher Ki-67 index, and loss of maturational gradient in MMs.¹⁷¹ In a comparison of typical Spitz nevi and non-Spitz MM, p16 was retained and Ki-67 was minimally expressed in the Spitz nevi.¹⁷² It would appear that p16 is expressed in most Spitz nevi, but it remains a point of some disagreement whether p16 reliably differentiates a Spitz nevus from AST and SPMM.^173,174 In terms of AST and SPMM, p16 loss is quite variable from 15% to 25% of cases. The retention or loss of p16 is dependent upon the heterozygous or homozygous loss of 9p21 (p16, CDKN2A) since one copy of the gene is haplosufficient for p16 expression.^175,176 When there is homozygous loss of 9p21, Lee et al.⁹⁵ reported a significantly increased risk for recurrence in the AST. In terms of Ki-67 (MIB-1), it is generally expressed in a low fraction of nuclei in Spitz nevi (2% or less) whereas AST and SPMM are greater than 5% to 10%, but once again, the single case exceptions exist of a Spitz nevus with 5% to 10% nuclear positivity. In general, most Spitz nevi have a gradient effect of HMB-45 expression with minimal reactivity in the smaller melanocytes toward the base of the biopsy or excision.

We have previously discussed to some extent the molecular aberrations associated with the Spitz nevus and the other spitzoid melanocytic lesions (Table 2). Comparative genomic hybridization and fluorescent in situ hybridization are 2 molecular techniques which have been most widely applied to the study and diagnosis of these difficult borderline lesions.^{90,94,161,171,177–185} Table 5 is an attempt to summarize the various observations regarding the copy number aberrations across the spectrum of Spitz and spitzoid melanocytic lesions and conventional MM. More recently, microRNA profiling has been evaluated to determine whether expression patterns may serve to discriminate one spitzoid lesion from another.¹⁸⁶

At present, it is questionable whether any consensus will emerge over the ability to reliably differentiate one atypical Spitz lesion from another.^94,95,187 Several authors have opined that the existing perspective on the spitzoid melanocytic lesions should undergo modification to a risk-based approach.¹⁸⁸ On the other hand, Piepkorn has stepped back to declare that the “Spitz nevus is melanoma” which was thought to be the case from the onset.^189,190 Urso has proposed that the spitzoid tumors (ST) from the Spitz nevus to spitzoid melanoma should be graded from ST1 to ST3 based upon histopathologic features and possible molecular findings to acknowledge that these lesions exist on a biological continuum and possibly we can overcome the problems in the varied terminology of these lesions.^93,191

Footnotes

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

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