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Editorial |

Genomic Rearrangements in Unusual and Atypical Melanocytic Neoplasms

Thomas Wiesner, MD1,2
[+] Author Affiliations
1Memorial Sloan-Kettering Cancer Center, Human Oncology and Pathogenesis Program, New York City, New York
2Department of Dermatology and Venereology, Medical University of Graz, Graz, Austria
JAMA Dermatol. 2016;152(3):260-262. doi:10.1001/jamadermatol.2015.3501.
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Melanocytes can give rise to a variety of benign and malignant neoplasms that are characterized by distinct clinical features, histopathological appearances, and biological behavior. In most melanocytic lesions, the clinical and histopathological distinction between benign (melanocytic nevus) and malignant (melanoma) is relatively easy. However, there exist unusual melanocytic neoplasms whose biological behavior can be difficult to predict with certainty owing to their ambiguous clinical and pathological features. This may lead to underdiagnosis or overdiagnosis of melanoma, or to diagnosis as “melanocytic tumor of uncertain malignant potential” or “melanocytic lesion with severe atypia.” The lack of agreement, even among experts, in determining the biological behavior of these lesions is well documented in the medical literature.1

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Frequent Genomic Aberrations in Cutaneous Melanocytic Neoplasms

A, Common acquired nevi usually show BRAF hotspot mutations; congenital nevi NRAS hotspot mutations. B, Cutaneous melanoma show BRAF hotspot mutations (BRAF subtype) in about 50%; NRAS, HRAS, or KRAS mutations (RAS subtype) in 25%; and NF1 (NF1 subtype) loss 10% of cases. The “triple wild-type melanoma” subtype is a heterogeneous subgroup of melanoma with infrequent driver mutations, such as KIT, GNAQ/GNA11, CTNNB1, or genomic rearrangements. C, A third very heterogeneous group of melanocytic tumors includes rare entities of melanocytic neoplasm, such as blue nevi and related neoplasms; spitzoid lesions; deep-penetrating nevi; or pigmented-epithelioid melanocytoma. This heterogeneous subgroup shows a pattern of genomic aberrations very different from melanoma or common acquired and congenital nevi, underlining that these melanocytic lesions are biologically distinct. Blue nevi frequently harbor mutations of GNAQ, and less often of GNA11. Spitzoid neoplasms show translocations involving the kinases ALK, ROS1, NTRK1, BRAF, RET, and MET in up to 50% of cases. Desmoplastic Spitz nevi frequently show HRAS mutations. Spitzoid lesions with large epithelioid cells, often combined with a regular nevoid melanocytes, often show loss of BAP1 and are associated with a hereditary tumor predisposition syndrome.

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