Malignant melanoma is a common type of skin cancer. It is usually diagnosed in the elderly patient and rarely encountered in children. Nevertheless, pediatricians should be aware of malignant melanoma in childhood (MMC), a disorder associated with mortality rates of up to 20%. Clinical and histological features have to be considered to distinguish MMC from much more common benign lesions, but straightforward diagnoses may be difficult to achieve. Unfortunately, diagnostic delays are related to poorer outcomes. The mainstays of therapy are the wide local excision of early-stage melanomas and lymph node dissection, if necessary.
Pediatric melanomas tend to arise from pre-existing nevi but may develop de novo . They may develop on any area of the skin but are most commonly found on the limbs and trunk . MMC derive from pigment-carrying cells and thus may be of dark brown color, but tumors observed in the pediatric population are often amelanotic . Most are superficial spreading melanomas, which appear as flat, slowly growing lesions with irregular pigmentation and borders. They tend to enlarge radially . The second most common subtype of MMC is nodular melanoma, which usually presents as a rapidly expanding nodule whose surface may be ulcerated  . Spitzoid melanomas account for a minority of cases but are particularly problematic because they resemble benign Spitz nevi with regard to their morphological and histological features   . Diameters >1 cm, asymmetry, ulceration, cytological atypia of epithelioid or spindle-shaped melanocytes with a nest-like growth pattern, high mitotic activity in the dermis, scarce maturation, and the involvement of subcutaneous fat are characteristic of spitzoid melanoma and are rarely observed in a typical Spitz nevus, but these features may apply to atypical variants of the latter.
- Skin Lesion
Physicians should be aware of skin lesions and full-layer biopsy should be obtained in suspicious skin lesions. Patients with congenital melanocytic nevi should also be followed up cautiously. Copyright: © 2020 Turkish Archives of Pediatrics. [ncbi.nlm.nih.gov]
Facial skin lesions. Purplish areas of spiderlike veins may appear on your nose and upper lip. Diarrhea. Frequent, watery stools sometimes accompanied by abdominal cramps may occur in people who have carcinoid syndrome. Difficulty breathing. [mayoclinic.org]
Cordoro et al (2013) have suggested adding additional ABCD detection criteria for skin lesions in children : A: Amelanotic (the lesion is skin coloured or red) B: Bleeding, Bump C: Colour uniformity D: De novo, any Diameter Melanoma in a congenital [dermnetnz.org]
On the other hand, pediatric patients may present with a wide variety of benign skin lesions, including, but not limited to, congenital nevi, dysplastic nevi, and Spitz nevi. [symptoma.com]
In the first place, details on the development of suspicious lesions have to be obtained: MMC may fulfill the so-called ABCD criteria of malignant melanoma, which comprise Asymmetry, Border irregularity, Color variegation, and Diameter >6 mm  . However, about 60% of MMC patients aged <10 years and 40% of those in adolescence do not meet the aforementioned criteria . The high incidence of such atypical presentations has led to the definition of alternate ABCD features, namely Amelanosis, Bleeding and Bumps, uniform Color, De novo and Diameter <6 mm . Evolvement, the E criterion, is a feature of virtually all melanomas. It has been recommended to use both classical and newly defined ABCD criteria to facilitate the early recognition of MMC .
As becomes clear, the phenotypic heterogeneity of MMC poses a major challenge when it comes to differentiating benign lesions from melanoma. In fact, a reliable diagnosis of MMC cannot be made unless tissue samples are obtained and microscopically examined. While full-thickness punch biopsies are preferred for specific locations, excisional biopsies are generally recommended for suspicious lesions . Besides the examination of native samples, immunohistochemical staining should be carried out to dispel any doubts as to the origin of tumor cells. It is particularly helpful in case of atypical MMC, e.g., if pigmented granules cannot be observed. Melanocytes typically express HMB-45, Ki-67, melanoma antigen/MART-1, and S100 protein. Fluorescence in situ hybridization is another tool commonly used to differentiate between adult melanoma and benign nevi, whereby the former typically exhibit alterations in chromosomes 1, 6, 7, 9, 10, 11, 17, and 20. Evidence supporting the usefulness of fluorescence in situ hybridization for the diagnosis of MMC is scarce, and some authors discourage from using it in the pediatric population  . Regardless of the age of the patient, tumor cells should be characterized regarding their genetic background. The presence of mutations in genes like BRAF and NRAS suggests susceptibility to specific molecular-targeted therapies.
If at all possible, the primary tumor should be surgically removed in its entirety. Surgical margins of 1-3 cm should be obtained, depending on the depth of invasion and anatomical location. While therapeutic lymph node dissection is an essential part of any curative intent, prophylactic lymph node dissection is not usually carried out. However, sentinel lymph node biopsies may be realized, and complete lymph node dissection should be considered in case of sentinel node-positive melanoma . The National Comprehensive Cancer Network recommends sentinel lymph node biopsies in case of tumor thickness >0.75 mm and ulceration or a mitotic rate >1/mm^2 and in case of tumor thickness >1 mm regardless of additional features .
Adjuvant therapies should be considered and may consist in the administration of chemotherapeutic agents, immunotherapy, and/or molecular-targeted therapy . However, clinical trials on the safety and efficacy of determined treatment regimens are generally limited to adult patients and exclude the pediatric population. Dacarbazine as well as cyclophosphamide, vincristine, and dactinomycin have been applied to small series of pediatric patients suffering from advanced-stage melanoma, which yielded promising results . Another of the few compounds tested in children is pegylated interferon α-2b . Radiation therapy plays a limited role in MMC treatment and is mainly used in a palliative setting . In light of the lack of alternatives, patients diagnosed with advanced-stage MMC should be included in clinical trials whenever possible.
Because recurrence may occur years after the initial diagnosis of MMC, patients should undergo regular follow-ups over prolonged periods of time .
Despite optimum surgical interventions and adjuvant therapy, recurrence occurs in a quarter of MMC patients and mortality rates may be as high as 20%  . According to other studies, the disease-specific overall survival rate approximates 90% . Distinct parameters should be considered before prognosticating the outcome in an individual case   :
- Lymph node metastasis is an unfavorable prognostic factor and decreases the likelihood of long-term survival to <70%. The presence of distant metastases is even more predictive of survival, with median survival times of patients with stage IV disease being <1 year.
- The probability of lymph node involvement negatively correlates with the patient's age.
- While a vertical growth phase indicates a high risk of metastasis, melanomas that show a radial growth phase are less likely to spread to lymph nodes and distant organs.
- Additionally, tumor thickness has been found to be significantly associated with the outcome. Survival is poorest among patients with tumors that measure >2 mm in thickness.
- Ulceration has been identified as an unfavorable prognostic factor.
Distant metastases primarily develop in the central nervous system .
While the triggers of MMC development remain unknown in the majority of cases, a number of demographic, dermatological, and environmental risk factors has been identified. These comprise Caucasian descent, fair skin, blonde or red hair, facial freckling, light eye color, the inability to tan on exposure to the sun and the tendency to burn with ultraviolet radiation, a medical and/or familial history of melanoma, giant congenital nevi, dysplastic nevi, a large number of benign nevi, as well as conditions interfering with DNA repair. About the latter, both inherited immunodeficiency and acquired immunosuppression have been shown to increase the risk of MMC . Beyond that, individuals suffering from xeroderma pigmentosum have a 5% risk of developing MMC before reaching adulthood   . Mutations in genes CDKN2A and CDK4 predispose to early-onset melanoma, but the majority of carriers is first diagnosed with skin cancer during mid-adulthood .
Malignant melanoma is a common kind of skin cance. Its incidence has been estimated to be 10-15 and 35 per 100,000 inhabitants of Europe and North America, and Australia and New Zealand, respectively . However, <2% of affected individuals are children or adolescents. From another point of view, this type of neoplasm accounts for <3% of malignancies in this age group . Highest incidence rates have been reported in Australia, where 8 of 1,000,000 children are diagnosed with MMC each year. In the Northern hemisphere, the annual incidence of pediatric melanoma is an order of magnitude lower .
According to current knowledge, there is no single pathway of MMC cancerogenesis. Still, the genomic profile of most MMC comprises alterations in either of the following pathways  :
- The Ras/Raf/MAPK pathway. The regulation of cell growth, differentiation, and apoptosis depends on this pathway and is disturbed in case of mutations in genes BRAF, NRAS, and MEK, among others. Oncogenic driver mutations typically affect the BRAF gene in cases of conventional adult-subtype MMC, while NRAS mutations are often detected in pediatric melanomas arising from large congenital nevi. In general, MMC development is favored by an overactivation of the Ras/Raf/MAPK pathway.
- The pathway comprising p16, cyclin-dependent kinase 4, D-type cyclins, and retinoblastoma protein. Activating mutations of CDK4 as well as inactivating mutations of CDKN2A and RB1 trigger a common pathway of cancerogenesis . Such mutations may be acquired or inherited.
- Telomerase reactivation. If telomere shortening is countered by an aberrant expression of the TERT gene, replicative senescence is avoided, and cells gain the ability to proliferate in an uncontrolled manner. Under physiological conditions, the TERT gene is silenced in somatic cells.
- The PTEN-PI3K pathway, which regulates growth, proliferation, and survival.
Degenerated melanocytes tend to accumulate mutations affecting the aforementioned pathways, but the order of their acquisition may vary from patient to patient.
Because mutations induced by ultraviolet radiation are assumed to play key roles in the pathogenesis of MMC, parents and children should be educated on preventive measures. They should be informed about the importance of using sunscreen, wearing long-sleeved clothes and wide-brimmed hats, and avoiding the full midday sun.
Malignant melanoma is a common type of skin cancer, but it is rarely diagnosed in children. Because MMC largely resembles adult melanoma with regards to invasiveness, metastasis, and mortality, it is important to raise awareness for this type of pediatric cancer. Most cases are sporadic, with only a minority of children being genetically predisposed to MMC development. High-risk susceptibility genes are those associated with xeroderma pigmentosum, CDKN2A, and CDK4, and molecular biological studies allow for the identification of carriers of pathological variants. By contrast, it remains difficult to assign specific causes to individual cases of sporadic MMC. In this context, a variety of risk factors has been identified and can be avoided by adopting preventive measures such as limiting sun exposure. It is generally assumed that exposure to ultraviolet radiation has a cumulative effect, which leads to an increased risk of sporadic melanoma in adulthood . However, this may not apply to individuals carrying low-risk susceptibility genes, many of which have not yet been identified or characterized concerning their implication in melanoma development. Pediatric melanoma may thus be classified as a multifactorial disease, with distinct conditions triggering different pathways of cancerogenesis. This is reflected in the clinical variability of MMC, which complicates the diagnosis of the disease. The differentiation of pediatric melanoma from much more common benign lesions poses a major challenge to pediatricians, oncologists, and pathologists, but is crucial to assure an early diagnosis, adequate treatment, and optimum outcome.
Malignant melanoma is a common type of skin cancer. It is usually diagnosed in the elderly and rarely encountered in children. On the other hand, pediatric patients may present with a wide variety of benign skin lesions, including, but not limited to, congenital nevi, dysplastic nevi, and Spitz nevi. It is very difficult to distinguish these entities from malignant melanoma in childhood (MMC), and a reliable diagnosis of the latter requires the cooperation of experienced oncologists and dermatopathologists. Nevertheless, parents and elder children may significantly contribute to the early diagnosis of the disease. One of the key features of MMC is evolvement, i.e., growing or otherwise changing moles may be suspicious of skin cancer and warrant a visit to the dermatologist. MMC may arise from pre-existing nevi, but this is not an exclusion criterion. Furthermore, pediatric melanomas are not necessarily of dark brown color. They may be amelanotic, be skin-colored or red. The clinical heterogeneity of MMC poses a major challenge to the treating pediatrician, and the disease can only be diagnosed after the microscopic examination of tissue samples. Sometimes, such samples are obtained by an excisional biopsy, which also serves as treatment. However, the surgical removal of the primary tumor may not be sufficient to achieve cure. Similar to adult melanoma, MMC may metastasize to regional lymph nodes and distant organs. Diagnostic imaging is generally used for tumor staging, to find out whether lymph nodes or other tissues show signs of metastasis. If no such signs are detected, sentinel lymph node biopsies may be carried out. Here, tissue samples are obtained from apparently unaffected lymph nodes to be further evaluated under the microscope. In sum, pediatric patients diagnosed with malignant melanoma have a favorable prognosis if the disease is diagnosed early, before reaching a depth of >2 mm and prior to the formation of metastasis.
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