2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

GENETIC ALTERATIONS IN CHILDHOOD MELANOMA
lence of approximately 1%. 34 The risk of malignant transformation
of congenital nevi increases with the size of the
nevus. In a review of 289 published cases of large congenital
nevi (more than 20 cm in diameter), melanoma developed
within a congenital nevus in 34 patients (12%). 35 The
clinical or molecular factors that lead to the transformation
of these lesions are unknown.
Secondary Proliferations
Secondary proliferations within a congenital nevus can
occur and are often difficult to histologically classify as being
malignant or benign. The results of CGH analysis of 29
congenital nevi and associated benign and malignant proliferations
showed no aberrations in the typical congenital
nevi, in congenital nevi of increased cellularity, or in congenital
nevi with benign proliferation. Additionally, seven of
nine cases of congenital melanocytic nevi with proliferations
simulating nodular melanoma predominately contained either
gains or losses of entire chromosomes. This finding
differs from that in melanoma in which fragments of various
chromosomes are detected. The pattern of chromosomal
abnormalities between the nodular lesions and melanoma
was also different. In contrast, the six cases of melanoma
arising in congenital nevi had multiple cytogenetic aberrations
in a pattern that was indistinguishable from that of
melanomas not associated with congenital nevi. 36 These
findings suggest that the type of genomic instability in
atypical nodular proliferations differs from that predominat-
Author’s Disclosures of Potential Conflicts of Interest
ing in melanoma and that CGH may be a useful tool in
distinguishing between the two entities.
RAS/RAF/MAPK Pathway Alterations
Some genes reported to be associated with melanoma,
including p53, p16, and CDK4, do not appear to be altered in
these proliferative lesions within a congenital nevi. 37 NRAS
mutations, however, are frequent in congenital nevi: 26 of 32
cases of congenital nevi in one series and 10 of 17 cases in
another had NRAS mutations. 37,38 Reports of BRAF mutations
in congenital nevi are conflicting. For example, Yazdi
and colleagues 32 and Pollock and colleagues 39 detected
BRAF mutations in six of 13 congenital nevi and six of seven
congenital nevi, respectively. In contrast, Bauer and colleagues
38 found no BRAF mutations in a series of 32 cases of
congenital nevi. They speculate that the discrepancy between
their findings and others may be due to selection bias
because they chose only lesions present at birth, but others
may have also considered nevi appearing in the first year of
life. It is well-documented that more than 80% of acquired
nevi have BRAF mutations. 39 The absence of BRAF mutations
would support the hypothesis that nevi that develop in
utero, in the absence of ultraviolet exposure, are genetically
distinct from nevi that develop after birth.
A better understanding of the embryonic development of
congenital nevi and their transformation to benign and
malignant lesions may provide some insight into the etiology
of melanoma that develops in childhood in the absence of
these lesions.
Employment or
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Author
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Fariba Navid Schering-Plough
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