Clinical acumen key for identifying pediatric melanoma

Timely diagnosis of melanoma in children requires that dermatologists maintain a high index of suspicion, recognizing that these malignancies are rare in the pediatric age group and may have diverse presentations with atypical clinical features.

Fortunately, accurate diagnosis of melanoma is being improved by advances in molecular diagnostics, while better understanding of the biologic behavior of atypical melanocytic lesions in children has led to changing recommendations for sentinel lymph node biopsy.

These issues were highlighted by speakers providing an update on management of pediatric pigmented lesions at the American Academy of Dermatology’s summer meeting.

Dr. HawrylukDiscussing the prevalence and clinical presentations of melanoma in the pediatric population, Elena B. Hawryluk, M.D., Ph.D., notes that pediatric melanoma accounts for only 1% to 3% of all cases of melanoma. In addition, dermatologists should recognize that the conventional ‘ABCDE’ criteria that help in diagnosing melanoma in adults are lacking in 40% to 60% of pediatric melanomas.¹

“Be aware that pediatric-specific ‘ABCD’ criteria for melanoma have been proposed that incorporate the following prominent features: amelanotic, bleeding or bump, color uniformity, and de novo growth, and these should be considered for melanoma detection in addition to those lesions that are suspicious based upon adult criteria,” says Dr. Hawryluk, assistant professor of dermatology, Harvard Medical School, Boston, Mass.

Furthermore, melanoma in children can present in diverse ways, including as uveal or acral melanoma, congenital melanoma representing maternal metastatic disease, melanoma in immunosuppressed patients, and melanoma with unknown primary.

Dr. Hawryluk points out that recent research is revealing characteristic genomic alterations for some of the diverse presentations of melanoma in children.  For example, melanomas arising from giant congenital melanocytic nevi have been found to have NRAS mutations, which are also characteristic of congenital nevi. In addition, kinase fusions have been found in Spitzoid melanomas and neoplasms, while adolescents with “conventional” melanomas have BRAF and somatic single-nucleotide variations that are consistent with UV damage.

“Genetic testing has yet to have a significant impact on the clinical management of melanoma in children,” Dr. Hawryluk says. “However, increased understanding about the genomic features of pediatric melanomas holds the promise for informing diagnosis, prognosis and new treatment strategies.”

Refining the diagnosis

Pedram Gerami, M.D., says recent advances in molecular diagnosis for melanocytic neoplasms is the result of a combination of improved ability to genomically characterize tumors as well as the acquisition of long-term follow-up for specific subsets of melanocytic neoplasms that have been genomically annotated.

Previously, molecular diagnostic evaluations were based on a simple paradigm in which the finding of genetic alterations, either gene copies or gene deletions, was considered highly suspicious for melanoma. More recently, as the result of increasing experience applying molecular diagnostic tests to the evaluation of atypical melanocytic neoplasms in children and pediatric melanoma, dermatopathologists are realizing that the spectrum of possible changes in benign tumors is much broader than suspected.

Dr. Gerami“Based on this new information, we have been developing more refined genetic criteria to more accurately identify lesions that have the potential for aggressive behavior versus those that are more likely to be benign despite having a worrisome appearance according to our standard microscopic assessment,” says Dr. Gerami, professor of dermatology, pathology and pediatrics, Feinberg School of Medicine, Northwestern University, Chicago.

“These are valuable advances considering that histologically borderline melanocytic neoplasms that have the biologic potential for aggressive clinical behavior really account for just a small percentage of biopsied pigmented lesions in children. With these improvements in diagnosis, we can better individualize therapeutic decisions and potentially spare children who have benign lesions from receiving unnecessary intervention with aggressive surgery and immunotherapy or chemotherapy.”

The refined molecular analyses are based on fluorescent in situ hybridization or comparative genomic hybridization and look for highly specific genetic abnormalities. In particular,  homozygous deletion of the CDKN2A gene has been associated with a higher likelihood of metastatic in histologically borderline melanocytic neoplasms of childhood.

“Although this is not the only marker of concern, lesions with this finding are clearly in a higher risk category, and we are now recognizing that the presence of a broad range of other genetic alterations may be seen in indolent lesions,” Dr. Gerami says.

Revisiting indications for SLNB

New research findings have also led to a change in the use of sentinel lymph node biopsies (SLNB) for the diagnostic evaluation of children, says Cassandra M. Kelleher, M.D., surgical director, Fetal Care Program and Neonatal Intensive Care Unit, Massachusetts General Hospital, Boston, Mass.

Historically, SLNB was considered standard for the workup of children with atypical or severely atypical melanocytic lesions considering the uncertain behavior of those tumors. However, recent data suggest that a positive SLNB in that setting for children does not have prognostic significance nor is complete lymph node dissection (CLND) performed because this does not confer a survival advantage.

Dr. Kelleher“We are finding that the risk of having pigmented cells in the lymph nodes is higher in children than in adults, and that the finding of pigmented cells in the lymph nodes does not necessarily translate into worse outcomes,” Dr. Kelleher explains.

She cites a review conducted by researchers at Stanford University that found SLNB positivity rates of 20% among children with melanoma and 33% among those with lesions designated as melanocytic tumors of uncertain malignant potential.² In the latter subgroup, there were no recurrences after surgical excision of the primary lesion nor any deaths during a mean follow-up duration of 22 months. In contrast, within the melanoma subgroup there were several recurrences and one death related to disease progression during a mean follow-up of 35 months.

The recommendation against SLNB also applies to children with atypical spitz lesions for which the rate of SLNB positivity is even higher. In a recent systematic review that included data from almost 550 patients with Spitzoid lesions, the SLNB positivity rate was 40%, and the 5-year survival rate for individuals with a positive SLNB was 99%.³

“SLNB is still indicated, however, for children with lesions diagnosed as Spitzoid melanoma,” Dr. Kelleher says.

She points out that the shift in recommendations for SLNB in children has important ramifications as it is sparing many children from unnecessary morbidity.

“Treatment when the SLNB is positive involves performing CLND that is associated with risks including seroma, lymphedema, and infection,” Dr. Kelleher explains.

“In addition, avoiding SLNB minimizes upstaging and thereby moves children who would be found to have a positive SLN out of a therapeutic pathway that would also include high doses of interleukin or interferon.”

References

1. Cordoro KM, Gupta D, Frieden IJ, McCalmont T, Kashani-Sabet M. Pediatric melanoma: results of a large cohort study and and proposal for modified ABCD detection criteria for children.  J Am Acad Dermatol. 2013;68(6):913-925.

2. Berk DR, LaBuz E, Dadras SS, Johnson DL, Swetter SM. Melanoma and melanocytic tumors of uncertain malignant potential in children, adolescents and young adults-the Stanford experience 1995-2008. Ped Derm. 2010;27(3):244-254.

3. Lallas A, Kyrgidis A, Ferrara G, et al. Atypical Spitz tumours and sentinel lymph node biopsy: a systematic review. Lancet Oncol. 2014 15(4):e178-183.