Key points

Introduction

It is common for parents of pediatric patients to request evaluation of a “lesion” that is new, changing, or concerning in some way. The lesion may be plainly visible to a parent seeking more information, or concern may be related to a rising general overall awareness about melanoma and skin changes. Diagnosis and management of pigmented lesions, particularly pediatric dysplastic nevi and Spitz nevi, can be challenging. In this article, we provide an overview of pigmented lesions in the pediatric population, including melanoma, and management of melanoma risk factors and melanocytic nevi in children.

Introduction

It is common for parents of pediatric patients to request evaluation of a “lesion” that is new, changing, or concerning in some way. The lesion may be plainly visible to a parent seeking more information, or concern may be related to a rising general overall awareness about melanoma and skin changes. Diagnosis and management of pigmented lesions, particularly pediatric dysplastic nevi and Spitz nevi, can be challenging. In this article, we provide an overview of pigmented lesions in the pediatric population, including melanoma, and management of melanoma risk factors and melanocytic nevi in children.

Pediatric melanoma

Melanoma in children is rare. According to the Surveillance, Epidemiology, and End Results (SEER) program, which houses national cancer registry information that has been collected since the 1970s in several states and metropolitan areas, there were 1317 cases of childhood and adolescent melanoma diagnosed between 1973 and 2009. Only 104 cases were identified among children up to 9 years of age, and a large majority of pediatric cases (1230) were among white persons, corresponding to an incidence rate of 6 per 1,000,000 individuals. The analysis revealed an overall increase in pediatric melanoma by approximately 2% per year, with greatest increases among girls aged 15 to 19, and people with low ultraviolet (UV)-B exposure based on geographic locations, where those who live in these areas often get intermittently intense UV exposure. Examination of all pediatric neoplasms among SEER data between 1992 and 2004 found an overall pediatric melanoma incidence of 4.9 per 1,000,000 individuals. Although this incidence is very low, the annual percentage change of 2.8% makes melanoma one of only a few pediatric neoplasms with significantly increased rates during this time period.

Although a diagnosis of melanoma among pediatric patients is rare, it carries a similar prognosis and clinical course as adult melanoma. Histopathologic prognostic factors include Breslow depth of melanoma, ulceration, mitotic rate, and presence or absence of lymphovascular invasion. It is especially important that the tissue is reviewed by a pathologist who is comfortable with the histopathology of skin from pediatric patients, as banal pediatric Spitz nevi and related tumors may harbor features concerning for melanoma, as discussed in this article.

Although melanoma disease course is similar between children and adults, clinical characteristics of pediatric melanomas do not always follow the typical “ABCDE” detection criteria of asymmetry, border irregularity, color variegation, diameter larger than 6 mm, and/or evolution ( Fig. 1 ). Cordoro and colleagues published a retrospective study of 70 cases of melanoma or ambiguous melanocytic tumors treated as melanoma from 1984 to 2009 and found that the most common pediatric melanoma characteristics are amelanosis, bleeding, “bumps,” color uniformity, diameter variability, and de novo development. Among 10 pediatric patients who succumbed to disease in their series, 90% were aged 11 to 19 years, 70% had amelanotic lesions, and 60% had at least one risk factor for melanoma. It is important to be cognizant of changing skin lesions and have a higher index of suspicion for patients with melanoma risk factors.

Dermatoscopic image of invasive melanoma, which was detected by conventional ABCDE criteria.

Melanoma risk factors

Pediatric patients with inherent melanoma risk factors should be identified and counseled to minimize external factors that can further increase their risk of developing melanoma. Examples of inherent risk factors that are nonmodifiable include age, pigmentation, nevi pattern, genetics and family history, and coincident medical conditions. Although risk of melanoma among pediatric patients is overall quite low, it increases with advancing age. Patients with a pigmentation phenotype of Fitzpatrick I (fair skin with blonde or red hair) are at highest risk, followed by individuals who burn easily, tan poorly, and freckle. A systematic meta-analysis of observational studies of melanoma risk factors identified an increased melanoma risk for physical attributes such as blue eye color (relative risk of 1.47 vs dark), fair skin color (2.06 vs dark), red hair color (3.64 vs dark), and high density of freckles (relative risk of 2.10).

A 1997 case-control study by Tucker and colleagues demonstrated the increased melanoma risk in adults with nevi. Risk is increased among patients with large numbers of banal nevi, such that having many small nevi increases risk approximately twofold, and having both small and large banal nevi imparts a fourfold increased risk. A personal history of having a single dysplastic nevus increases melanoma risk by twofold, whereas having 10 or more dysplastic nevi increases melanoma risk by a factor of 12. Even the presence of a scar confers an independent increase in melanoma risk, as it suggests the possible prior removal of a nevus. Melanoma enters the clinical differential when examining a pediatric patient who has clinically atypical or dysplastic nevi, a large congenital melanocytic nevus, or a Spitz nevus, which is discussed in further detail later in this article.

Having a primary family member with melanoma is associated with a relative risk of 1.74 of developing melanoma. Fetal malignant melanoma is very rare and most often presents as melanoma from maternal metastasis. Having a parent with multiple melanomas corresponds to a relative risk of 61.78. Patients with 2 or more primary relatives with dysplastic nevi and a history of melanoma should prompt consideration of Familial Atypical Multiple Moles and Melanoma (FAMMM) syndrome, which often carries mutation in CDKN2A gene or the related signaling pathway, and is associated with increased rates of pancreatic and renal cell carcinoma. Both cutaneous and ocular melanomas are identified among kindreds with BAP1 genetic mutation. Risk for development of melanoma is increased in patients with genetic diseases affecting photosensitivity or those affecting DNA repair mechanisms, such as xeroderma pigmentosum; these patients are diagnosed with melanomas at a 5% rate, with 65% of the melanomas distributed to photo-exposed areas. Immunosuppression is another important consideration that increases melanoma risk among patients with AIDS, cancer, and transplantation.

It is important to identify patients with increased melanoma risk due to the intrinsic factors described previously, to counsel them to avoid extrinsic risk factors such as sunburns or exposures to medications or relevant activities (including photo exposure and tanning practice). Medications, such as psoralens, can artificially increase damage caused by UV rays, and a number of common phototoxic medications, including tetracycline antibiotics, cetirizine, propranolol, naproxen, and fluoxetine, lead to increased UV damage and sunburns. Long-term use of medications that cause immune system suppression can impact melanoma risk in a dose-dependent manner: among organ transplantation recipients, melanoma occurs in 14% of patients who received transplantation as a child, compared with 6% in adulthood. Transplant patients may also take chronic systemic antifungal prophylaxis with voriconazole, which causes photosensitivity and is associated with melanoma. Cutaneous surveillance is warranted, and the development of cutaneous neoplasms may prompt revision of the immunosuppression and prophylactic therapeutic regimens.

Excessive sun exposure and indoor tanning are exogenous risk factors for the development of melanoma. The World Health Organization’s International Agency for Research on Cancer classified UV radiation as carcinogenic to humans in 2009. An overall increased melanoma risk is associated with sporadic intermittent sun exposure, blistering sunburns, and self-reported sunburns. All patients should be counseled to avoid sunburns through the use of sunscreen, sun-protective clothing, or sun-avoidance practice, as discussed further later in this article.

Indoor tanning is an extrinsic UV radiation exposure that contributes to increased melanoma risk, and is an important risk for adolescent patients. There are increasingly large studies and evidence shows more convincingly the link between indoor tanning and risk of melanoma. In 2012, Zhang and colleagues used a large, well-characterized female nursing cohort to demonstrate a dose-response relationship between the use of tanning beds and melanoma risk (11% increased risk among participants who used tanning beds 4 times per year).

Despite increasing state legislation to prevent indoor tanning among minors ( Fig. 2 ), Mayer and colleagues reported that in the 100 most populated American cities, indoor tanning was used in the preceding year by 17.1% of adolescent girls and 3.2% of adolescent boys. Adolescent tanning was more common among white, older, and female adolescents, and those who have a parent who practices indoor tanning, a larger allowance, and live close to a tanning facility. Among non-Hispanic white female high school students, 29.3% reported having tanned in the past, with 16.7% having tanned during the preceding year. Counseling against indoor tanning is an important intervention to mitigate risk for skin cancer and melanoma.

Indoor tanning restriction for minors, effective October 2013.

( Courtesy of John Adamson, diymaps.net.)

Congenital nevi

Congenital nevi are traditionally defined as melanocytic nevi that are present at birth, and have historically been classified based on final, adult size ( Fig. 3 ). In 2013, new recommendations were prepared for the categorization of cutaneous features of congenital melanocytic nevi with division of medium (M1: 1.5–10 cm, M2: >10–20 cm), large (L1: >20–30 cm, L2: >30–40 cm), and giant (G1: >40–60 cm, G2: >60 cm) sized nevi. These investigators put forth additional descriptors with moderate to excellent expert interobserver agreement to describe the anatomic localization, color heterogeneity, surface rugosity, presence of hypertrichosis, presence of dermal or subcutaneous nodules, and number of satellite nevi (none, 1–20, >20–50, or >50). At the time of birth, one can expect a congenital nevus to reach at least large classification based on the growth of the nevus in proportion to the child’s growth if its diameter is larger than 9 cm on the head, or larger than 6 cm on the body. Although small and medium-sized congenital nevi are skin-limited conditions, the presence of a large congenital nevus carries increased risk of both skin and systemic abnormalities.

Congenital nevi of medium ( A ), large ( B ), and giant ( C ) classification.

Among all congenital nevi, the exact increase in melanoma risk is estimated at less than 1%, and among patients with small and medium-sized congenital nevi, this risk is virtually entirely after the patient reaches puberty. A number of studies have estimated the increase in melanoma risk associated with large congenital nevi, but given the rarity of these nevi and accumulation at referral centers, in addition to historic interpretation of proliferative nodules as melanomas, older estimates of melanoma risk may be artificially inflated. In 2013, Vourc’h-Jourdain and colleagues performed a meta-analysis of studies published between 1966 and 2011 to examine melanoma risk for patients with congenital melanocytic nevi larger than 20 cm in size, and reported that 2% of 2578 patients developed melanomas, of which 74% had a nevus larger than 40 cm in size and 94% had satellite nevi.

The most prevalent systemic manifestation of large congenital nevi is neurocutaneous melanocytosis, in which melanocytes are present in the leptomeninges. This may be an asymptomatic or symptomatic phenomenon, and is not easily ascertained by available imaging studies. The risk for neurocutaneous melanocytosis is greatest among patients with congenital nevi larger than 40 cm in size and those with multiple satellite nevi; conflicting studies also implicate a posterior axial location of the congenital nevus. Among patients with large congenital nevi, additional abnormalities include complications attributed to nevus size and location, such as obstruction of orifices, urinary tract anomalies, musculoskeletal limitations, and neurologic sequelae of neurocutaneous melanocytosis.

Congenital nevi change over time, and some changes may prompt reevaluation. First and foremost, they are expected to grow in size in proportion to the patient’s growth over time. Some may develop overlying hypertrichosis, which can be removed by clipping or shaving the hairs if desired. The surface of the congenital nevus may appear darker or lighter in color over time, undergo verrucous surface changes, or become overall thicker in depth. Nevi on the scalp are reported to spontaneously involute over time; it is advisable to monitor scalp nevi without intervention during a patient’s first 2 years of life to allow for maximal improvement before any surgical manipulation. Large and giant congenital nevi are also known to develop “proliferative nodules” within the nevus, which may reveal atypical histology but have reassuring genomic changes that are distinct from those of melanomas based on comparative genomic hybridization. The decision to excise all or part of a congenital nevus is based on multiple factors, including personal and family history that may confer increased risk of melanoma, ease of monitoring, psychosocial factors, and risk of postoperative complications (such as scarring, contractures, and cosmesis), as excision of the nevus does not completely remove the risk of melanoma. Further, as many congenital nevi have large size and depth, ablative surgery or complete excision of deeper layers is often nearly impossible to achieve, and pigment recurrence in the setting of scarring poses great challenge to the pathologist reviewing reexcised tissue.