Track

Clinical Studies

Abstract

Epigenetic profiling of primary melanoma by whole-genomic methylation analysis may be grouped into classes exhibiting hypermethylation of CpG islands (CpG island methylator phenotype [CIMP]), intermediate methylation (IM) or low methylation (LM).  Prior studies suggest that CIMP melanomas may have worse melanoma-specific survival, independent of other prognostic factors, relative to LM melanomas.  However, the cytological features including nuclear atypia grade of CIMP melanomas have not been characterized.  We assessed the nuclear grade of 88 cutaneous primary melanomas with whole-genome methylation data.  Melanoma nuclear grades were based upon nuclear size and variability, nuclear membrane contour irregularities, chromatin distribution, and number and size of nucleoli.  Grade 1 nuclei resemble those of benign nevi while grade 3 show extreme nuclear irregularities and grade 2 nuclei appearance fall in between that of grade 1 and grade 3.  Among the 88 melanomas, grade 1, grade 2, and grade 3 nuclear atypia were observed in 3 (3%), 32 (36%), and 53 (60%) of cases, respectively.  Higher nuclear grade was statistically significantly associated with CIMP:  93% of CIMP tumors (13/14) had grade 3 nuclear atypia, compared to only 61% (25/41) and 46% (15/33) of IM and LM tumors, respectively (CIMP vs IM Fisher P=0.05; CIMP vs LM Fisher P=0.007).   Higher nuclear grade was also associated with increased Breslow thickness (P=0.007) and presence of mitoses (P=0.0003).  Our data indicate that higher nuclear atypia grade is strongly correlated with higher methylation status and other poor prognostic features in cutaneous melanoma.