This case report illustrates that molecular analysis can be very helpful in the differential diagnosis between a second primary melanoma and a melanoma metastasis. We chose for mutational analysis of the
BRAF gene and the
ras proto-oncogenes
NRAS and
HRAS, because these genes are frequently involved in cutaneous melanocytic lesions, with a reported total mutation frequency for
NRAS or
BRAF of 82% in cutaneous melanoma [
4]. Furthermore, these mutations are described to occur early in tumorigenesis, before the development of metastasis [
4,
11]. We detected in all three tumor samples an
NRAS codon 61 mutation (c.182A>G, p.Gln61Arg).
NRAS mutations are known to occur in up to 30% of all cutaneous melanoma cases, the most common being mutations in NRAS codon 61 [
4,
7,
11]. In contrast,
NRAS mutations have been reported to be absent in primary uveal melanoma [
3,
15]. The
NRAS mutation thus strongly supports the metastatic nature of the intraocular melanoma in our patient. The finding of the same somatic mutation in
CDKN2A in both cutaneous and intraocular melanoma confirms the metastatic nature of the disease in this patient. In contrast to
NRAS mutations that are limited to codon 61 and codon 12 in cutaneous melanoma, somatic
CDKN2A mutations are much more tumor specific and thus are not expected to be identical in two different primary melanomas [
7]. Furthermore, activating
CDKN2A mutations are described to be very rare in primary ocular melanomas [
9,
13].
Eskandarpour et al. reported specific activating mutations in
NRAS codon 61 in 95% of primary hereditary cutaneous melanomas (20/21), but in only 10% of sporadic cutaneous melanomas (1/10) [
5]. Therefore, the presence of a somatic
NRAS codon 61 mutation might indicate a familial predisposition to melanoma instead of a clonal relationship.
Discriminating between a second primary intraocular melanoma and metastatic disease is of prognostic importance. Intraocular metastases of melanoma are associated with a poor prognosis with a mean interval between diagnosis of the intraocular metastasis and death of 8.8 months [
17]. In contrast, survival in patients diagnosed with a primary intraocular melanoma is more variable, with a reported 5-year cumulative survival rate of up to 60% [
12].