News & Press
What’s New in Pediatric Melanoma?
Guest blog post by Vernon K. Sondak, MD (Department of Cutaneous Oncology, Moffitt Cancer Center), with Jane L. Messina, MD (Departments of Cutaneous Oncology and Anatomic Pathology, Moffitt Cancer Center) and Alberto S. Pappo, MD (Department of Oncology, St. Jude Children’s Research Hospital):
“What’s changed in pediatric melanoma?” is a question Dr. Messina and I posed in a recent editorial1 written about a journal article2 authored by Dr. Pappo and his team (all three of us have been members of the Melanoma Research Foundation’s Pediatric Melanoma Steering Committee for the past several years). The answer we gave to that question was “pretty much everything,” and in today’s blog we will talk about exactly what we mean by that. First of all, an awful lot has changed in melanoma in adults over the past 10 years,3 with new surgical approaches and new drugs combining to decrease the death rate from adult melanoma nearly 30% in the past 5 years with less long-term surgical side effects than ever before. Almost all of these improvements have influenced our treatment of melanoma in children under 18 years of age, even though relatively few children have been enrolled in clinical trials. But while some cases of melanoma diagnosed in teenagers are similar in every way to adult melanoma, most cases of melanoma diagnosed earlier in childhood are biologically and pathologically distinct from adult melanomas. Visually, they often don’t have the classic ABCD criteria widely seen in adult melanoma.4 Under the microscope, the appearance of childhood melanoma also can be very different,5 with even experienced pathologists sometimes unable to agree about whether a biopsy specimen represents melanoma or a benign mole called a Spitz nevus. Often, the term “Spitzoid” is used to refer to the fact that these cases in some way resemble Spitz nevi under the microscope.6 These challenging cases are called “atypical Spitz tumors” or other names conveying uncertainly about what the expected behavior of a pediatric lesion would be.7 And it is here, in understanding the molecular characteristics of benign and malignant skin lesions in children, where some of the biggest changes of all have come for pediatric melanoma.
The bottom line is that melanocytic lesions with Spitz-like features in children fall into 3 main categories, and for each category the terminology has now been defined: (1) melanoma similar to adult melanoma, which we now call “Spitzoid melanoma”; (2) melanoma with multiple distinctive DNA changes, which we now call “Spitz melanoma”; and (3) atypical but not definitely melanoma, still termed “atypical Spitz tumor.” We’ve learned this through applying a variety of diagnostic tests when confronted with diagnostically challenging childhood lesions. These tests include immunohistochemistry, fluorescence in situ hybridization (FISH), comparative genomic hybridization (CGH), gene expression profiling (GEP), testing for specific mutations (for example, BRAF, NRAS, HRAS and TERT promoter mutations) and ‘next generation sequencing’ (NGS) of the lesion’s DNA. In their recent article in the medical journal Cancer, Dr. Pappo and his colleagues studied 70 skin lesions from children 18 or younger with some or all of these techniques. The results of this study confirmed how much we can learn from these advanced molecular tests.
Delving a little further into Dr. Pappo’s study, some children in their series turned out to have melanomas with genetic changes that were similar to adult melanoma, including frequent BRAF mutations, and we now know that when we see these characteristic genetic changes in what otherwise seems to be an atypical Spitz tumor, then it really represents a Spitzoid melanoma. Using this new terminology, these Spitzoid melanomas behave pretty similar to adult melanomas in most respects. Many of the rest of the atypical Spitzoid lesions tested had genetic changes called “fusions” that are quite uncommon in adult melanomas. These fusions, in and of themselves, do not prove that a mole is malignant, and that is where the other tests like CGH or FISH can be helpful. When these atypical tumors have lots of other molecular abnormalities, we can confidently say they are indeed malignant Spitz melanomas (not just Spitzoid). But these Spitz melanomas seem to have a better prognosis than most other types of melanoma, including the Spitzoid type, even though they often spread to lymph nodes and occasionally beyond. Still, even with the most comprehensive testing, a small group of atypical Spitz tumors remain, and we will have to develop new tests before we can completely eliminate all of the uncertainty about how these atypical tumors will behave. And keep in mind that no matter how thoroughly a biopsy sample is tested, if that biopsy comes from only a small part of the lesion, then additional tissue from excision of the mole and in some cases removing a sentinel node or nodes can lead to a more definitive diagnosis.7
To summarize, pathologists sometimes have difficulty determining whether a mole biopsied from the skin of a child is benign or malignant. New molecular technologies have helped pathologists identify pediatric melanomas, but there are still some atypical moles that cannot be definitely classified as benign or malignant. With further research, we hope we can decrease the number of these atypical tumors and improve the treatment for all children with moles and melanoma.
In the second part of this blog, to be released separately, we will talk about the advances in treatment of pediatric melanoma once the diagnosis of malignancy has been made.
Life-saving advances in pediatric melanoma research are made possible by supporters like you. In honor of Pediatric Melanoma Awareness Month, please consider a tax-deductible donation today:
1Sondak VK, Messina JL. What’s new in pediatric melanoma and spitz tumors? Pretty much everything. Cancer 2021; Jul 6. doi: 10.1002/cncr.33749. Published online ahead of print.
2Pappo AS, McPherson V, Pan H, et al. A prospective comprehensive registry that integrates molecular analysis of pediatric melanocytic lesions. Cancer 2021; Jul 6. doi: 10.1002/cncr.33750. Published online ahead of print.
3Curti BD, Faries MB. Recent advances in the treatment of melanoma. N Engl J Med 2021;384:2229-2240.
4Cordoro KM, Gupta D, Frieden IJ, McCalmont T, Kashani-Sabet M. Pediatric melanoma: results of a large cohort study and proposal for modified ABCD detection criteria for children. J Am Acad Dermatol 2013;68:913-925.
5Bartenstein DW, Fisher JM, Stamoulis C, et al. Clinical features and outcomes of spitzoid proliferations in children and adolescents. Br J Dermatol 2019;181:366-372.
6Gerami P, Busam K, Cochran A, et al. Histomorphologic assessment and interobserver diagnostic reproducibility of atypical spitzoid melanocytic neoplasms with long-term follow-up. Am J Surg Pathol 2014;38:934-940.
7Sondak VK, Reed D, Messina JL. A comprehensive approach to pediatric atypical melanocytic neoplasms, with comment on the role of sentinel lymph node biopsy. Crit Rev Oncog 2016;21:25-36.