Pathology and genomics of pediatric melanoma: A critical reexamination and new insights

Abstract

The clinicopathologic features of pediatric melanoma are distinct from those of the adult counterpart. For example, most childhood melanomas exhibit a uniquely favorable biologic behavior, save for those arising in large/giant congenital nevi. Recent studies suggest that the characteristically favorable biologic behavior of childhood melanoma may be related to extreme telomere shortening and dysfunction in the cancer cells. Herein, we review the genomic profiles that have been defined for the different subtypes of pediatric melanoma and particularly emphasize the potential prognostic value of telomerase reverse transcriptase alterations for these tumors.

Keywords: childhood melanoma; melanoma arising in association with large/giant congenital nevi; pediatric melanoma; spitzoid melanoma.

Figure 1.

Photomicrographs of hematoxylin and eosin-stained (H&E) sections and immunohistochemical stains for p16 and BRAF V600E in an adult subtype melanoma from a peri-adolescent patient. Malignant melanoma, nodular type (A; H&E, scanning magnification), composed of confluent nests of epithelioid malignant melanocytes (B, H&E 20×). Immunohistochemical analysis shows loss of p16 expression (C) and positive staining for BRAF V600E (D) in the melanoma cells. The melanoma harbored a BRAF^V600E and a TERT promoter mutation.

Figure 2.

Photomicrographs of H&E stained sections and interphase fluorescence in situ hybridization (FISH) with RET and ROS1 dual color, break-apart probe from patients with pediatric spitzoid melanocytic tumors. A-C: Pediatric spitzoid melanoma with predominantly spindle cell features (A, H&E 4×; B, H&E 40×) harboring RET fusion. FISH image (C) shows split red and green signals, consistent with RET rearrangement. D-F: Pediatric spitzoid melanocytic tumor with epithelioid and spindle cell features (D, H&E 4×; E, H&E 20×) harboring ROS1 fusion. FISH image (F) shows separate red and green signals in several nuclei, consistent with ROS1 rearrangement.

Figure 3.

Photomicrographs of H&E sections and TERT mRNA in situ hybridization (ISH) in a melanoma and in a proliferative nodule arising in association with giant congenital nevi. A-C: Melanoma consisting of malignant small round cells in the dermis within a giant congenital nevus (A, H&E 4×; B, H&E 40×). TERT mRNA ISH shows numerous punctate intracellular signals (C), consistent with high TERT mRNA levels. D-F: Proliferative nodule arising within a giant congenital nevus in deep soft tissue, characterized by cellular features, mitotic activity (D, H&E 2×; E, H&E 40×), and no significant levels of TERT mRNA detected by ISH (C).