Dysplastic/Clark naevus in the era of molecular pathology

Abstract

Dysplastic naevus has been a controversial entity since its first description by Clark in 1978. Despite a recent paradigm shift from the initially proposed notion that dysplastic naevus is a precursor to melanoma, its management has been increasingly more aggressive in the last decade. The latter is due to an unresolved uncertainty regarding its biological nature which necessitates further clarification. Recent molecular genetics, epigenetic and transcriptomic discoveries have revealed that a subset of dysplastic naevi exhibits a genomic profile which is intermediate between that of benign naevus and melanoma. This group of lesions often shows somatic mutations in non-V600E BRAF, NRAS and TERT and hemizygous deletion of CDKN2A gene as well as upregulation of genes involved in proliferation, cell adhesion and migration, and epidermal and follicular keratinocyte-related genes. These new genomic insights suggest that a proportion of dysplastic naevi have a greater propensity to evolve to melanoma; however, the clinical and histopathological features of this proposed intermediate category are still to be elucidated by further research.

Differential Immunoexpression of BRAF/V600E, Senescence Markers, PTEN, and T-type Calcium Channels in Acquired Naevi According to their Histopathological and Dermoscopic Classification

“…In conclusion, molecular alterations related to oncogenes, senescence, proliferation and others were described in DN ( 3 ), and in dermoscopically reticular vs globular naevi ( 4 , 8 ). However, the distribution of these or other alterations among the main CAN and DN histopathological and dermoscopic patterns has not been specifically addressed.…”

“…Regarding other biomarkers, Ki67 and hTERT expression were significantly higher and p16 significantly lower in DN vs IN. Previous studies indicated an increase in proliferation markers and p16 losses in DN and intermediate melanocytic lesions ( 3 , 5 ) and a greater immunoexpression of hTERT in DN than CAN ( 12 ) or, more specifically, in DN vs IN ( 13 ). Moreover, TERT promoter mutations were described as early alterations in inter-mediate lesions ( 5 ).…”

“…A single DN progresses to melanoma in either a similar or a slightly higher frequency than that of common acquired melanocytic naevi (CAN) ( 3 ). There is some controversy ( 4 ) regarding whether these lesions share alterations (mutations in non-V600E/BRAF , NRAS and TERT promoter, hemizygous deletion of CDKN2A ( 5 )) with CAN and melanoma, as well as upregulation of genes involved in cell proliferation, adhesion, migration, and epidermal/follicular keratinocyte-related genes ( 3 ). Moreover, T-type calcium channel (TT-C) expression increases from CAN to DN and melanoma and could be a biomarker of tumour progression ( 6 ).…”