Melanocytic aggregates: Melanoma does not necessarily develop de novo

Key Points

International report - A recent study suggests that banal melanocytic aggregates, such as those observed in simple nevi, may very well represent precursor lesions of malignant melanoma.

"'When in doubt, take it out.' That has always been the message that dermatologists hear again and again, and are firmly advised to follow.

"This appears to be sound advice, as melanocytic aggregates may be the beginnings of melanoma," says Ophelia E. Dadzie, M.D., M.R.C.P., of the department of dermatology, Chelsea and Westminster Hospital, London.

Most dermatologists believe that a dermal nevus and melanoma often have a similar genetic profile, suggesting that they probably start from these precursor lesions.

In past studies, Dr. Dadzie and Jag Bhawan, M.D., professor of dermatology and pathology and head of the dermatopathology section at Boston University School of Medicine, looked at normal skin excisions and found incidental foci of nevi (subclinical nevi).

Further, when looking at primary melanomas under the microscope, small foci of what looked like banal nevi could be seen.

Clinical study

Dr. Dadzie and Meera Mahalingam, M.D., Ph.D., F.R.C.Path., of the dermatopathology section of the department of dermatology at Boston University School of Medicine, Boston, recently conducted a study to determine whether the histologic distinction between banal and malignant nevomelanocytic populations relates to differences in the prevalence of mutations in genes significant in the etiopathogenesis of malignant melanoma.

In the study, BRAF and RAS mutations were ascertained in 18 cases of primary cutaneous malignant melanoma contiguous with banal nevic aggregates using a combination of laser capture microdissection and gene sequencing.

Results

Results showed that 12 of 18 cases (67 percent) exhibited a mutation in at least one of four genes, and BRAF V600E appeared to be the most commonly mutated gene in both the nevic aggregate (seven of 18 cases, or 39 percent) and the melanoma (four of 18 cases, or 22 percent). Interestingly, a relatively high prevalence of KRAS mutations was seen in the nevic aggregate (five of 18 cases, or 28 percent).

BRAF and RAS mutations appeared to be mutually exclusive, with only three of 18 cases (17 percent) demonstrating a mutation in both genes (nevic aggregate only).

"Though this was a relatively small study, the evidence seems to suggest that malignant melanoma does not necessarily develop de novo.

"Furthermore, it appears that banal nevi that were once thought to be just that may be the very precursors of melanoma," Dr. Dadzie tells Dermatology Times.

'Valuable clues'

According to Dr. Mahalingam, the results of the study provide valuable clues; however, in order for this to have a clinical impact, larger studies are required to confirm these findings.

In another recent study, Dr. Mahalingam and colleagues found that in melanomas and nevi harboring the BRAF V600E mutation, the tumor suppressor IGFBP7 is switched off in melanomas, whereas it is maintained in nevi (Wajapayee N, Serra R, Mahalingam M, Green MR. Oncogenic BRAF induces senescence through an autocrine/paracrine pathway mediated by the secreted protein IGFBP7. Cell 2008; 132:363).

"Extending this to the current study, ascertaining expression of this protein may be pivotal to providing an explanation for the etiopathogenesis of melanomas arising in the context of a banal nevus.

Molecular diagnostics

According to Dr. Dadzie, clinical pathology is slowly but surely moving toward an era of molecular diagnostics, and the future approach to a lot of melanomas should include genetic profiling.

"I believe that the dawn of this diagnostic avenue being used a standard tool is upon us. This is relevant, especially as we can develop a more targeted therapy as well," Dr. Dadzie says.

Disclosures: Drs. Dadzie and Mahalingam report no relevant financial interests.