Anatomy of the Dermis and Epidermis

The skin is a morphologically and functionally complex tissue providing protection against physical elements by its anatomic structure and potential for immune responsiveness. The outermost layer is the stratum corneum or horny layer, which is composed of devitalized keratinocytes (see Fig 71-1). While the dermal layer is a derivative of the paraxial mesoderm, embryologically the epidermis is of ectodermal origin.

The basal layer of the epidermis is the site of mitotic activity leading to the proliferation of keratinocytes. This basal layer consists of columnar cells anchored to the basement membrane via hemidesmosomes and anchored to the dermis via penetrating fibrils (see Fig. 71-1). Interspersed between the basal cells reside melanocytes that are dendritic cells and are the source of melanin (see Fig. 71-2). Melanocytes are not secured via desmosomes or tonofilaments. Functional units (epidermal melanin units) are composed of a melanocyte and the keratinocytes to which it is responsible for the transfer of melanin. Melanosomes are the cytoplasmic organelles that result from the fusion of vesicles containing tyrosinase and vesicles containing the structural melanosomal proteins, both of which are generated by the melanocyte’s endoplasmic reticulum. Differential skin pigmentation amongst individuals results from the variable production of melanosomes, their content and rate of degradation, and not on numbers of melanocytes. The absence of tyrosinase prevents formation of melanosomes and results in albinism. The melanosomes migrate from the perinuclear area along microtubules to the dendritic tips where these are phagocytized by the keratinocyte. As the squamous cells differentiate, the melanosomes are degraded by lysosomal enzymes.

The more superficial layer of dermis is the papillary dermis, which interacts with the epidermis via a basement membrane and sends interdigitating papillary and neurovascular structures to support the epidermis. The appendages to the skin, the hair follicles, sweat, sebaceous and apocrine glands, originate in the dermis. The fibroblast-derived matrix of collagen and elastin reside primarily in the deeper, reticular dermis.

Congenital Nevi

CMN are pigmented lesions of variable size that develop during the first few months of life. They are the consequence of failure of melanocytic migration into the epidermis. These lesions grow proportionally with the infant and are generally categorized as small (<1.5 cm), medium (1.5–20 cm), and large (>20 cm). Those especially large lesions (>40 cm) are also referred to as a garment nevus, giant hairy nevus, or bathing trunk nevus since they tend to cover large truncal areas in confluence (Fig. 71-7). Although the pigmentation and surface are initially uniform and flat, the lesions evolve into thick, dark, and often hair-covered lesions. Histologically, the melanocytic cells in congenital nevi are located deeper than in acquired nevi (Fig. 71-8). The absence of superficial involvement may explain why transformation is often not noticed until late in its development. The incidence of transformation is greatest in the large or giant congenital nevi, and low in small to medium size lesions. The size of the congenital nevus therefore becomes the key element in discussing management.

Excision of small and medium CMN can be delayed or avoided in favor of lifelong observation. The estimated lifetime risk of melanoma in these lesions is estimated at 1%, and most occur after puberty. Biopsy may be of value in stratifying the risk of malignant degeneration. If histological examination shows the more superficial variant, continued observation is warranted, since any transformation is likely to be associated with epidermal changes that will be apparent on close follow-up or self-examination. If the histological variant demonstrates deep melanocytes, then prophylactic excision is recommended.

The management of large or giant CMN is more controversial. The melanoma risk for these lesions is increased and estimated to be 5–10% over a lifetime with 50% of this risk during the first five years of life.3,4 The highest risk lesions are associated with the nevus that is situated over the posterior trunk, greater than 40 cm in maximal dimension, and associated with satellite nevi. Melanoma in these patients can arise from the deep dermal layer or even originate from sites distant from the skin such as the CNS (2.3% in one study⁵) or retroperitoneum.⁴ These patients are also at risk for neurocutaneous melanosis (7% in one study⁵) and CNS malformations such as Dandy–Walker malformation, defects of the vertebra, skull, and intraspinal lipomas. Screening MRI of the brain and spinal cord is recommended during first six months of life in these patients.⁵ Conversely, two-thirds of patients with neurocutaneous melanosis have giant CMN and the others have multiple nongiant lesions. The prognosis for patients with symptomatic neurocutaneous melanosis is extremely poor even in the absence of malignancy.⁶ The increased routine surveillance with MRI during infancy for children with large CMN has identified those with asymptomatic CNS involvement, and hopefully will impact the care and outcome of these patients in a positive manner. These patients are also at risk for other soft tissue malignancies such as rhabdomyosarcoma⁷ or neurofibrosarcoma (peripheral nerve sheath tumor).

Since operative resection of these extensive lesions is often not feasible and never completely eliminates the risk for melanoma, these patients need close medical surveillance. Areas of epidermal change within the nevus should be biopsied. However, caution must be exercised in interpreting the histological results, since the proliferative nodules may resemble melanoma, but behave in a benign manner.⁸ Features useful in differentiating a cellular nodule from melanoma include: (1) lack of high grade uniform cellular atypia; (2) lack of necrosis within the nodule; (3) rarity of mitoses: (4) evidence of maturation; (5) lack of pagetoid spread; and (6) no destructive expansile growth.⁹

When operative intervention is needed, collaboration with colleagues with added expertise in the use of tissue expanders, rotational flaps, and skin grafting may be helpful. In one study, the mean age for intervention was 5.1 years and took an average 1.3 years to complete resection and reconstruction in these patients with large and giant CMN.¹⁰ While the authors expressed a preference for earlier intervention, they acknowledged that the average age of the patients referred to them was 4.7 years, and many had already undergone an operative procedure. Over half of the cohort required more than one operative intervention and 22 of 40 patients needed skin grafts. Also, 18 patients benefitted from tissue expanders and autologous cultured skin replacements.

Acquired Nevi

Acquired nevi are benign neoplasms of the skin which appear after 6 months of age and persist through the fourth decade, after which many disappear. They are most frequently located on sun-exposed areas and are rare on the breast or buttock. Common to all these acquired nevi is that they are less than 6–8 mm in diameter, symmetric in shape, have a homogeneous surface and even pigmentation, and have a regular outline with a sharply demarcated border. On close inspection, they may have some pigmentary stippling.

Histologically, these acquired melanocytic nevi are divided into subtypes based on the location of the nests of nevus cells, and this feature corresponds with certain clinical findings (see Table 71-2). Junctional nevi tend to be flat with brown/black pigmentation and the nevus cells are located at the dermal–epidermal junction. When the nevus cells extend from the junction into the dermis, the lesion is described as a compound nevus. Clinically, this corresponds to a lesion that is slightly raised and pigmented brown/black. When the nevus cells migrate completely into the dermis, the lesion is an intradermal nevus, which is raised and typically not pigmented. In general, the deeper the nests of nevus cells, the more raised and less pigmented the lesion. (i.e., dark flat lesions vs raised tan lesions). The temporal evolutionary path of nevi was originally described by Stegmaier and explains the clinical observations of progressive change within individual nevi or their resolution.¹¹ Newer nevi tend to be small and flat (junctional), and either develop a raised profile or disappear with time as a consequence of fibrosis. In one study, when the nevi on adolescents were followed over a 4-year period, there was a net increase of 50% in total number of nevi, despite a complete regression in 15%.¹² This demonstrates the potential for active turnover in individual patients. Freckling and lighter colored skin are associated with increased numbers of nevi. In darker skinned individuals, nevi also develop, but are usually found on the palms and soles, unlike in the more fair complexioned individuals.

Sun exposure during childhood, especially when it is intense, intermittent, and not necessarily associated with sunburn, is a promoter for nevus development, and is the major environmental factor associated with the risk of melanoma. Recent evidence suggests that sunscreen use has led to a false sense of security in that it provides incomplete protection to UV rays.¹³ Sunscreen alone does not provide sufficient protection. Public health education must focus on the avoidance of midday sun and the use of physical barriers such as UV protectant clothing and hats.^13–16

The role for excision of these acquired nevi is limited when they are clearly defined by their age at presentation and the features described in Table 71-2. The natural evolution and changes in these common lesions should not be mistaken for malignant progression.

Atypical Nevi

Atypical nevi, previously referred to as dysplastic nevi or Clark’s nevi, are common lesions found in 5% of the population, and may occur either sporadically or in a familial pattern (Fig. 71-9). The onset of their first appearance is usually during adolescence on the sun-exposed areas of skin, and they continue to increase in number and size with age. Unlike the common acquired nevi, these lesions are usually larger than 5 mm (up to 15 mm), and have an irregular surface ranging from completely flat to flat with a raised center resembling a fried egg. The pigmentation usually is dark and irregular, and the border of the lesion is often irregular as well. These lesions are most common in persons with light skin and hair color. Ultraviolet light has been implicated in the transformation of melanocytes in these nevi.

When a patient has multiple atypical nevi or moles, they may be diagnosed with the atypical mole syndrome. While it can be normal to have up to 10 to 20 nevi, people with this syndrome may have in excess of 100 moles. Individuals with 50–100 nevi and one or more first- or second-degree relatives with melanoma are considered to have the familial atypical mole and melanoma (FAMM) syndrome that identifies them at significantly increased risk (approaching 100%) for the development of melanoma. It is important to note that the melanoma may arise de novo on any part of the body and not necessarily from a preexisting atypical lesion. Simple excision of an atypical nevus therefore does not obviate the patient from close dermatologic follow-up. In families with the FAMM syndrome, nevi arising on the scalp can be an early predictor for this syndrome, although the scalp nevus itself may involute with time. In these individuals, the nevi tend to be similar in appearance, the corollary being that a new nevus that varies in appearance or location should be regarded with suspicion. The ability of clinical health care providers as well as nonclinicians to identify the ‘ugly duckling’ has been found to be reliable.¹⁷ Routine surveillance examinations with photo documentation are recommended with dermoscopic (epiluminescence microscopy) evaluation of those nevi undergoing significant change. Dermoscopy has been shown to improve sensitivity and specificity with regard to detecting melanoma.¹⁸

Atypical nevi are not necessarily removed to confirm the histological pattern of atypia, but should be biopsied when melanoma is suspected. The biopsy should encompass a 1–2 mm rim of normal tissue and be sufficiently deep to allow to assess the depth of invasion in the event that melanoma is identified. The original designation of dysplastic nevus has been replaced with the term atypical nevus, and the pathologic description currently should use the term ‘nevus with architectural disorder’ and indicate the extent of cytologic atypia. The concordance between clinically atypical nevi and the histological findings of dysplasia is poor. These lesions are at the heart of much of the unfortunate controversy and misinformation that surrounds patients and referring physicians with terms and descriptions of atypia and dysplasia. These descriptive features have led to inappropriate re-excision of some lesions, and have even prompted sentinel lymph node biopsies for a completely benign process. Expert dermatopathologic review is essential for achieving the best care.

Specific Congenital or Acquired Melanocytic Lesions Requiring Distinction from Melanoma

Several melanocytic nevi are discussed separately due to their unique features, which frequently prompt their evaluation for malignancy. These lesions can be congenital or acquired, and are described in terms of their junctional, compound, or dermal location (Table 71-4). A recent review by Schaffer provides some practical advice regarding these specific lesions.¹³

Halo nevi (Sutton’s nevi) are unique lesions which appear between 6–15 years of age, and are typically located on the trunk or extremities. They appear as round or oval lesions, with a central area of pigmentation that may be tan to brown in color, and are surrounded by a rim of depigmentation (Fig. 71-10). Histologically, the central nevus is usually a compound or dermal nevus surrounded by a uniform infiltrate of T-lymphocytes. Pigmentation can be intermittent. Excision is limited to those that develop atypical characteristics within the pigmented part. There is no association with malignancy. These nevi cause clinical suspicion only because regressing melanoma may be gray or white.

A blue nevus is a benign proliferation of dendritic dermal melanocytes. Its etiology is attributed to a dermal arrest in embryonic migration of neural crest melanocytes that fail to reach the epidermis and thus create a hamartoma. This is a lesion with a large amount of pigment within the dermis, resulting in absorption of longer wavelengths of light and scattering of blue light known as the Tyndall effect. Two variants of blue nevi are distinguished based on their size: (1) the common blue nevus is usually less than 5 mm; and (2) the cellular blue nevus measures 1–3 cm.

The common blue nevus appears in adolescence and is most often located on the head and neck, the sacrum, and the dorsal aspect of the hands and feet. Given their dermal location, these lesions are usually nodular, and can be mistaken for nodular melanoma, except that there will be no precedent history of rapid growth. Dermatoscopy shows a uniform blue-gray pigment profile that helps distinguish the blue nevus from melanoma.

The cellular blue nevus usually presents on the scalp, buttock, sacrum, and face. It may be congenital or acquired. Histologically, it is located within the deep (reticular) dermis, and is a well-demarcated nodule. Cellular lesions may have occasional mitoses, but significant atypia and necrosis are absent. A potential for malignant degeneration exists only in these cellular lesions, and is clinically heralded by increase in size and ulceration.

The presence of multiple blue nevi should prompt consideration for the Carney complex of myxomas, spotty pigmentation, and endocrine neoplasias. The persistence of extensive dermal melanoses such as those found in Mongolian spots, especially when in a ventral distribution, should prompt evaluation for lysosomal storage diseases such as Hurler syndrome and GM1 gangliosidosis.

Spitz nevi are raised, often light or nonpigmented lesions (light tan-red or reddish-brown) that appear dome-shaped with either a smooth or a verrucous surface (Fig. 71-11). Histologically, these lesions are compound nevi, although pure junctional and pure dermal variants exist as well. Dermatoscopic examination shows a starburst pattern (Fig. 71-12). These lesions tend to occur on the face or lower extremities, and measure 0.3–1.5 cm in diameter. There is a slight female preponderance with 50% of these occurring in children under 10 years of age and 70% under 20 years of age. The increased red coloration is due in part to increased vascularity, with telangiectasia in the superficial dermis. The vascular surface features explain why these lesions are more prone to bleeding with minimal trauma.

The pigmented variant of the Spitz nevus is known as a nevus of Reed, and typically occurs on the leg of a young woman. The appearance of Spitz nevi may be quite sudden, prompting the concern for potential melanoma. Spitz nevi were previously classified as ‘benign juvenile melanoma,’ a misnomer which was responsible for the misconception that pediatric melanoma was less aggressive than the adult melanoma counterpart. Most Spitz nevi are completely benign; however, atypical clinical features such as a diameter greater than 1 cm, asymmetry, or ulceration should prompt complete excision. Most often, a young patient who has undergone a shave biopsy is referred for complete excision of the lesion so that it may be fully evaluated by a dermatopathologist. One must remember that one pitfall of a shave biopsy is that the most atypical portion of the lesion is examined and may incorrectly reflect the overall nature of the lesion. There is a spectrum of lesions from the benign Spitz nevus to the spitzoid melanoma. Those intermediate lesions with atypical histologic features have become the center of much controversy, and are often referred to as melanocytic or spitzoid tumor of uncertain malignant potential.

The clinical features of Spitz nevi can be complex, but they generally are reassuring when the lesion is uniform and symmetric. Histologically, the junctional nests of melanocytes have few or no mitoses. The nevus includes spindle cells and large epithelioid cells in variable architectural arrangements. Multinucleated cells may be present, but should not exhibit much pleiomorphism. Nucleoli are often prominent and rounded. Some of these features in another clinical context could be reminiscent of melanoma, which requires that these lesions be evaluated by dermatopathologists with significant experience in all of the elements of this variant. Those Spitz lesions with unusual histological features should be excised completely.

In approximately 10% of all cases, histological features within these lesions do not permit distinction between a Spitz nevus and a spitzoid melanoma. These atypical Spitz nevi then become diagnostic and treatment dilemmas. In these complicated instances, one might consider the safest approach would be to treat the lesion as a melanoma equivalent of the same depth. Berk et al. have reviewed the Stanford experience regarding these lesions.¹⁹ Although some surgeons have advocated for sentinel lymph node biopsy (SLNB) as a supplemental tool for categorizing the histologically indeterminate lesion, this approach has been strongly criticized as being unnecessarily invasive for the limited information gained. In the limited numbers of patients who underwent SLNB and were then treated with completion lymph node dissection (CLND) and chemotherapy, there was no disease recurrence.²⁰ Also, the current biologic and clinical evidence indicates that the presence of melanocytic lymphoid infiltrate does not predict clinical behavior, and may not even identify metastases or even malignancy as it does for melanoma.²¹

Several authors have recently reported their experience in the management of these confounding lesions. In a meta-analysis of 10 recently published series, 175 patients underwent SLNB and 67 were found to have positive SLN status (38%).²² However, this relatively high incidence of SLN positivity does not provide the prognostic information that it does for adult melanoma, and seriously questions the overall utility of SLNB. This is further emphasized by Ghazi et al., who found that on a median follow-up of 56 months, 90% of their patients are free of recurrence.²³ They suggest that therapeutic SLND should be limited to those patients with clinically palpable nodes, and patients who have positive SLN should simply be monitored with ultrasound (US) for recurrence or progression rather than being subjected to CLND. Another group reported on their patients treated without SLNB. Twenty-nine patients underwent resection of the primary lesion, and with a mean follow-up of 8.4 years (range 3.5–15.8 years), 14 had no recurrence.²⁴ An additional 10 patients had a shorter duration of follow-up (mean 2.8 years), and had no evidence of recurrence. Their recommendation for these atypical spitzoid tumors is excision with clear margins and careful clinical follow-up.

The nevus of Ito and nevus of Ota are congenital dermal melanocytic disorders that develop because of incomplete migration of melanocytes resulting in a hamartomatous lesion. These lesions are most commonly found in Asian populations. In the case of the nevus of Ota, the lesion appears along the distribution of the ophthalmic and maxillary branches of the trigeminal nerve on the face, and is evident as a blue-gray patch. These nevi may also involve the ocular and mucosal surfaces. The nevus of Ito involves pigmentation over the shoulder area and is often associated with a nevus of Ota. The pigmentation becomes more prominent with age and may be amenable to laser therapy.²⁵ Melanoma has been reported to arise infrequently in the nevus of Ota, but the association with glaucoma is important and should lead to ophthalmologic referral.²⁶

Nevi Occurring at Special Sites

A number of nevi occur at sites that have been particularly concerning for melanoma. They are now referred to as ‘lesions with site-related atypia that must be distinguished from their malignant counterpart’.²⁷ Atypical scalp nevi are a frequent cause for referral for excisional biopsy on the basis that they may be difficult to follow. They can also be markers for patients with the FAMM syndrome or dysplastic nevus syndrome. A recent observational study of 44 scalp lesions documented that they are morphologically active lesions during the childhood years, and suggested that the same principles for excision should apply as for other atypical nevi.²⁸

Acral nevi are found on the palms and soles. Although they may exhibit linear streaks, they must be viewed with suspicion if they have mottled pigmentation and are greater than 7 mm.²⁹ Longitudinal melanonychia are pigmented streaks emanating from the nail matrix and can be a normal variant that is most frequently seen in darker skinned individuals. Dark bands and those lesions that are wider than 6 mm, or associated with nail dystrophy, or extending beyond the nail fold, should be biopsied to exclude melanoma.^30,31 On mucosal surfaces, distinction must be made between labial melanotic macules which are benign lesions on the lower lip of women that resemble freckles but do not darken with sun exposure, and more concerning lesions in the oral cavity.³² In young women presenting with melanotic lesions over the vulvar area, it is important not to overtreat these generally benign lesions.³³

Specific Predisposing Conditions for Pediatric Melanoma

The diagnosis of melanoma is made in children in several discrete clinical contexts. Congenital melanoma is the least common, and is associated with transplacental transmission. It also may arise from a primary cutaneous lesion. The appearance of any rapidly growing, ulcerating, or bleeding lesion in the newborn should be evaluated promptly. However, the incidence of this clinical scenario is so low that projections about outcome are difficult to estimate, but the prognosis is generally poor. Confounding variables include reports of spontaneous regression and the presence of micrometastases that do not appear to correlate with survival.8,45

Melanoma associated with CMN has been well described and presents a unique set of clinical issues (Fig. 71-13). The lifetime risk for development of melanoma in patients with CMN is variably estimated between 5–40%.⁴⁶ More conservative estimates indicate a 5–10% lifetime risk, with half of this risk distributed within the first five years of life.^3,47 Two recent prospective studies of patients with giant CMN showed the incidence of melanoma during the first five years of life was between 3.3–4.5%.^48,49 Those patients with a posterior axial location and numerous satellite lesions have the greatest risk as compared to those with lesions restricted to the head and extremities.¹³

These tumors may originate from deep dermal sites and are often not visually apparent. Despite the sometimes ominous appearance of the satellite lesions, these have not been documented as the primary site for melanoma. Proliferative nodules within giant CMN often raise the specter of malignancy, but numerous authors caution against hasty conclusions in this clinical scenario.8,50 Neurocutaneous melanosis occurs in conjunction with large CMN and is the most common cause for nonepithelial melanoma. Although techniques for resection and reconstruction have improved such that disfigurement can often be avoided, these remain challenging operations. Moreover, there is no assurance in alleviating this risk for nonepithelial melanoma despite full-thickness removal of the CMN. In contrast, the smallest (less than 1.5 cm) CMN lesions are not associated with any increased risk for melanoma. It is within the intermediate group that little data exist to help guide management. At Massachusetts General Hospital, CMN lesions up to 5 cm have not been associated with melanoma in patients under 20 years of age.⁴⁶ Illig et al. reported melanoma arising in CMN lesions less than 10 cm only after 18 years of age.⁵¹ Rhodes and Melski calculated a lifetime risk of 2.5–5.0% in persons with small CMN living to 60 years of age.⁵²

While large and perhaps some intermediate-sized CMN help identify patients at risk for the development of melanoma, radical excisional therapy can be tempered by the recognition that cautious observation and selective biopsy can be an alternative therapy, especially since the melanoma can arise from sites other than the CMN. When resection is considered, preoperative planning allows for the optimal use of reconstructive techniques including skin and tissue expanders and a variety of rotational flaps or free tissue transfers in addition to skin grafts.

Other conditions predisposing to melanoma include patients with xeroderma pigmentosum in whom the inability to repair UV induced DNA damage results in a 2000-fold increased risk of skin cancer.⁵³ Patients with genetic immunodeficiency syndromes are reported to have a three- to sixfold increased risk.⁵⁴ Children on chemotherapy for childhood malignancies or children undergoing solid organ transplantation experience an increase in total nevi counts as well as the induction of atypical nevi.⁵⁵ Although neonatal phototherapy for hyperbilirubinemia has been demonstrated to induce an increased number of nevi, it is uncertain whether this will escalate the risk for future melanoma.⁵⁶ Unfortunately, it is important to remember that 60–80% of malignant melanoma in patients under 20 years of age occurs in the absence of known cutaneous risk factors.⁵⁴

Diagnosis

The difficulty in making the diagnosis of melanoma during childhood relates to a number of variables. The natural evolution of congenital and acquired nevi during childhood and adolescence often limits the effectiveness of adult data. Also, there is limited value to the mnemonic ABCDE (asymmetry, border irregularity, color variegation, lesion diameter greater than 6 mm and evolution) (Fig. 71-14) for a pigmented lesion since variegations and irregular shape are frequently associated with an atypical nevus. Specifically, the physical characteristics of giant CMN that predispose to melanoma arise in the deep dermal layers and extend within the deep subcutaneous tissues, rather than becoming apparent externally. Consequently, childhood melanoma may present in a markedly different manner from its adult counterpart. Recent growth, ulceration, or bleeding may be the most frequent presenting features. In contrast to the adult experience with thin (less than 1 mm) melanomas, pediatric melanomas are typically greater than 1.5 mm in thickness. This may be due to delays in diagnosis, a deeper origin within a CMN, and a higher incidence of nodular melanomas in children.³⁸ In one series of melanoma in children, the most common presenting symptoms were recent growth, pain, ulceration, itching, bleeding, and change in color in the lesion.⁵⁷ In the 13 patients, three had lesions that resembled pyogenic granuloma. Only one patient presented with evidence of metastatic disease. Eleven of 13 were nodular and only two were superficial spreading. The mean tumor thickness was 3.2 mm in this series.

In a series in children under age 12 years, the clinical parameters that favored melanoma were a rapid increase in size (55% of patients), bleeding (35%), or color change (23%) of a nodular lesion.⁵⁴ Less frequent signs or symptoms included a subcutaneous mass (6%), pruritis (15%), and enlargement of a regional LN (7%). In 7% of the patients where a melanoma developed in association with a preexisting nevus, the patients had no clinical symptoms.

A study of 33 prepubertal patients attempted to delineate the clinical features and outcomes of pediatric melanoma.³⁴ In this series, the sites of origin were most frequently the extremity (n = 15), trunk (n = 10), and head or neck (n = 8). Interestingly, 14 of 28 patients had amelanotic lesions and the majority of lesions were raised and resembled pyogenic granuloma.³⁴ Superficial spreading (n = 15) and the nodular melanoma subtypes (n = 9) were the most common lesions. The median lesional thickness was 2.5 mm.

The consistently thicker lesions in childhood melanoma suggest either a delay in diagnosis or reflect biologic characteristics such as the propensity for nodular melanoma and for lesions to arise from the deep dermal layers. Unfortunately, these lesions may be misdiagnosed initially. Only their sudden appearance and rapid growth over a few months may prompt biopsy. Therefore, despite the infrequency of this diagnosis, the clinician must consider melanoma in the differential diagnosis of cutaneous lesions in children.

The roles of clinical dermatoscopy, computer dermatoscopy (digital epiluminesence microscopy), and ultrasound imaging of the skin have been described for monitoring high risk adult patients.39,58–60 However, there are no current reports focusing on children.

Management of Histologically Confirmed Melanoma

Staging and treatment protocols of histologically confirmed melanoma are derived from the adult literature. The recommendations for extent of re-excision are based on the thickness of the tumor and generally requires a 0.5 cm margin for in situ lesions, a margin of 1 cm for lesions up to 2 mm, and 2 cm margins for lesions greater than 2 mm in thickness. SLNB is advised for lesions thicker than 1mm or those between 0.76 mm and 1 mm with ulceration or reticular dermal invasion (see Table 71-5). The new AJCC staging system is primarily based on: (1) Breslow tumor thickness with 1 mm, 2 mm and 4 mm indicating the current cutoffs for thin, intermediate, and thick lesions; and (2) histological features such as ulceration which is perhaps most important in the intermediate thickness group. Clarke’s levels are only taken into account in thin melanomas. Lymph node involvement is stratified by the number of nodes involved, and whether microscopic or macroscopic metastases are present. Finally, three subgroups of distant metastases are distinguished: (1) skin and soft tissue; (2) lung; (3) other visceral organs. Patients with visceral metastases have the worst prognosis. In this new classification, the serum LDH is used to further stratify risk. If elevation of the LDH is verified in the presence of either skin, soft tissue, or lung metastases, the prognosis is equivalent to that in patients with visceral metastases.⁶⁸

The standard imaging techniques used to identify potential metastatic disease sites include computed tomography (CT), magnetic resonance imaging and positron emission tomography (PET). PET-CT has been approved for this use as it has been demonstrated to be particularly helpful in identifying developing metastases.⁶⁹ The limitations in PET scanning continue to relate to the size of the lesion, such that it cannot compete with lymph node biopsy for nonpalpable lymph nodes.⁷⁰

The Role of SLNB

In adult melanoma therapy, SLNB has become a mandatory procedure in the current AJCC staging system to detect lymph node micrometastases. With a positive SLNB, the recommendation is to proceed with a CLND. A negative SLNB, however, does not guarantee lack of distant spread. It is evident that this algorithm protects against early locoregional recurrences, but does not have an impact on overall survival. These protocols have been applied to pediatric patients with melanoma and atypical melanocytic tumors. In one review, 20 patients under 21 years of age underwent SLNB for melanoma or atypical nevi.⁷¹ No complications occurred as a result of the SLNB, and results showed that positivity correlated with tumor thickness. Five of 15 patients with melanoma had a positive SLNB as did three of five with melanocytic proliferation. Seven of eight patients underwent CLND (one patient with blue nevus did not). Complications such as lymphedema and wound infection occurred with the completion lymphadenectomy in four patients. When this was further explored in a subsequent study, the investigators found a higher incidence of positive SLNB in a group of patients younger than 20 years with either melanoma or melanocytic lesions (40%) as compared to a group of adults (18%).⁷² None of the pediatric patients with a positive SLNB recurred while 25% of the adults did.

More recent series further document that positive SLNB is associated with a 10–15% of positive CLND and that the breakpoint in prognostic value appears to lie at puberty, with a higher incidence of SNLB in those <10years of age, but a worse prognosis for the older cohort.43,73–75 These series and others suggest that while SLNB is feasible, it may not be of sufficient value or benefit to the patient.⁷⁶ As in adults, SLNB provides prognostic value, but does not affect outcomes. Also, there is no survival benefit to immediate CLND vs. observation, and the morbidity of this second procedure must be considered carefully. The biological differences between pre-pubescent and older patients based on tumor thickness must somehow be related in part to local conditions including a relative difference in skin thickness, altered dermal immune reactivity, and perhaps altered lymphatic drainage thresholds.

Adjuvant therapies include chemotherapy, radiation therapy, and immunotherapy.⁷⁷ Despite the encouraging reports from the mid-1980s, the use of cytotoxic agents has a limited role in current adjuvant therapy. Combination protocols using cyclophosphamide, vincristine, and dactinomycin, or single agent dacarbazine and isolated regional perfusion with melphalan, were also reported to be effective, but did not provide for improved long-term outcomes. Radiation therapy has limited applicability and is primarily reserved for palliation. Most active trials and current research focus on immunomodulating agents, such as interleukin 2 (IL-2) and interferon alpha (IFN-α2b). In limited series, these agents have shown the ability to induce partial and even total remission.⁷⁷ The use of high dose IFN-α is limited to patients with high risk, resected tumors and involvement of the nodal basin. It appears that the early use of IFN-α contributes to improved relapse-free survival in these patients.³⁶ There have been conflicting reports about pediatric patients being able to tolerate high-dose interferon regimens. In one series, no dose reduction was necessary,⁷⁸ but was needed in 50% of patients in another series.⁷⁹ Vaccines have also been tried and consist of either polyvalent vaccines or defined melanoma antigens such as the ganglioside GM2, which is the most immunogenic ganglioside expressed on melanoma cells. More recent reports on the use of heat shock proteins as vehicles for the vaccines have been encouraging.^38,80 Further advances in our understanding of the germline and somatic mutations in melanoma are potential new therapeutic targets.⁸¹

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