melanocytic lesions

Types

 benign melanocytic lesions (benign melanocytic tumors)
 malignant melanocytic lesions (malignant melanocytic tumors)

Physiopathology

At a molecular level, the mitogen-activated protein kinase signaling pathway (MAPK signaling pathway) and PTEN/AKT signaling pathway are both involved in the growth control of melanocytic cells.

Activation of these pathways via somatic mutations in the RAS and RAF genes is thought to be one of the first steps in the development of common naevi.

RAF, RAS and GNAQ mutations lead to the development of naevi out ofmelanocytes. These mutations occur exclusive of each other. HRAS mutations are confined to Spitz naevi, and GNAQ mutations are found in blue naevi.

The next step is thought to be the development of a premalignant lesion from a pre-existent naevus or de novo. This stage is caused by progressive accumulation of genetic alterations with additional mutations in genes like CDKN2A or PTEN mutations and/or gains or losses of chromosome parts.

A point mutation (BRAF-V600E) in the BRAF gene in 7q34 is thought to be an early event in the genesis of naevocellular naevi and cutaneous melanomas derived from intermittent sun-exposed skin, and this mutation is thought to be induced by this intermittent type of sun exposure.

Melanomas derived from other sites (chronic sun-exposed or sun-protected sites) less often contain these BRAF mutations.

In addition, certain benign naevi such as blue naevi, Spitz naevi and congenital naevocellular naevi do not or rarely contain BRAF mutations, and instead in part contain other mutations, e.g. in the NRAS or HRAS genes.

Very recently somatic mutations of GNAQ, occurring exclusively in codon 209 (GNAQ-209) in the RAS-like domain, were found in uveal melanomas and blue naevi, both lacking BRAF or NRAS mutations.

Like mutations in BRAF, these RAS mutations and GNAQ mutations can cause MAPK activation and form an alternative route for melanocytic neoplasia.

All these mutations seem to be an early event in the development of melanocytic tumours and by themselves are insufficient to cause progression towards melanoma.

In further development from melanocytic naevus towards dysplastic naevus additional molecular alterations, like loss of wild-type INK4A and loss of PTEN, are implicated.

In progression towards melanoma additional genetic alterations such as loss of chromosome 6q, del11q, and gain of 7q have been described.

Molecular techniques such as array-based CGH have revealed that there are distinct pathways involved in the development of melanoma, with different genetic alterations in melanomas at different sites and with varying levels of sun exposure.

Copy number changes for discriminating between benign and malignant melanocytic lesions

CGH has demonstrated that most melanomas (96%) have multiple genetic aberrations (mean number of aberrations 7.5), while these are absent in common naevi see.

This could potentially allow differentiation of more than 96% of melanomas from naevi.

Only a specific subtype of benign naevus, so-called Spitz naevus, contains aberrations, which are virtually only single 11p gains.

Also in so-called proliferative nodules in congenital naevi in children, CGH could be helpful in assessing the diagnosis.

True melanomas arising in congenital naevi show CGH patterns comparable to typical melanoma, while atypical nodules contain numerical aberrations of entire chromosomes, which are seen only in a minority (5%) of melanomas.

BRAF mutations

Oncogenic BRAF mutations have been observed in both malignant melanoma and melanocytic nevi. The activation of the mitogen-activated protein kinase pathway (MAPK signaling pathway) may be a critical initiating step of melanocytic neoplasia,.

The fundamental difference between melanoma and nevi may lie in the inhibitory machinery for this oncogenic signaling. In addition, different genetic alterations identified in melanomas at different sites and with different levels of sun exposure have been shown, indicating that there are several distinct genetic pathways in the development of melanoma.

Different patterns of genetic alterations have also been identified among different kinds of melanocytic nevi.

While acquired nevi and small congenital nevi show a high frequency of BRAF mutations regardless of their anatomic localization, the mutations were rare in medium-sized congenital nevi and giant congenital nevi.

Spitz nevi show no BRAF mutations, while a subset of cases show HRAS mutations, often associated with a copy number increase of chromosome 11p.

See also

 muccosal melanoma

References (Genetics)

 Genetic alterations in melanocytic tumors. Takata M, Saida T. J Dermatol Sci. 2006 Jul;43(1):1-10. PMID: 16750612

 Genomic analysis of melanocytic neoplasia. Bauer J, Bastian B. Adv Dermatol. 2005;21:81-99. PMID: 16350439