Clinicopathologic Features of Incident and Subsequent Tumors in Patients with Multiple Primary Cutaneous Melanomas

Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Sydney, Australia.
Annals of Surgical Oncology (Impact Factor: 3.93). 09/2011; 19(3):1024-33. DOI: 10.1245/s10434-011-2058-8
Source: PubMed


0.6-12.7% of patients with primary cutaneous melanoma will develop additional melanomas. Pathologic features of tumors in patients with multiple primary cutaneous melanomas have not been well described. In this large, international, multicenter, case-control study, we compared the clinicopathologic features of a subsequent melanoma with the preceding (usually the first) melanoma in patients with multiple primary cutaneous melanomas, and with those of melanomas in patients with single primary cutaneous melanomas.
Multiple primary melanoma (cases) and single primary invasive melanoma (controls) patients from the Genes, Environment and Melanoma (GEM) study were included if their tumors were available for pathologic review and confirmed as melanoma. Clinicopathologic characteristics of invasive subsequent and first melanomas in cases and invasive single melanomas in controls were compared.
A total of 473 pairs comprising a subsequent and a first melanoma and 1,989 single melanomas were reviewed. Forward stepwise regression modeling in 395 pairs with complete data showed that, compared with first melanomas, subsequent melanomas were more commonly contiguous with a dysplastic nevus, more prevalent on the head/neck and legs than other sites, and thinner. Compared with single primary melanomas, subsequent melanomas were more likely to be associated with a contiguous dysplastic nevus, more prevalent on the head/neck and legs, and thinner. The same differences were observed when subsequent melanomas were compared with single melanomas. First melanomas were more likely than single melanomas to have associated solar elastosis and no observed mitoses.
Thinner subsequent than first melanomas suggest earlier diagnosis, perhaps due to closer clinical scrutiny. The association of subsequent melanomas with dysplastic nevi is consistent with the latter being risk factors or risk markers for melanoma.

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Available from: Marianne Berwick, Feb 25, 2014
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    • "Among others, family history of melanoma (presence of two or, mainly, three or more affected relatives) confers the highest risk for the development of the disease [3,5]. Nevertheless, patients with cutaneous melanoma present a higher incidence of second or even additional melanomas (risk seems to be highest in the first years after diagnosis of the first melanoma and decreases progressively with time) [6,7]. However, subsequent primary melanomas have been found to be significantly thinner than index lesions [8], possibly due to increased surveillance and not to differences in tumor biology [9-11]. "
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    ABSTRACT: Background Alterations in key-regulator genes of disease pathogenesis (BRAF, cKIT, CyclinD1) have been evaluated in patients with multiple primary melanoma (MPM). Methods One hundred twelve MPM patients (96 cases with two primary melanomas, 15 with three, and 1 with four) were included into the study. Paired synchronous/asynchronous MPM tissues (N = 229) were analyzed for BRAF mutations and cKIT/CyclynD1 gene amplifications. Results BRAF mutations were identified in 109/229 (48%) primary melanomas, whereas cKIT and CyclinD1 amplifications were observed in 10/216 (5%) and 29/214 (14%) tumor tissues, respectively. While frequency rates of BRAF mutations were quite identical across the different MPM lesions, a significant increase of cKIT (p < 0.001) and CyclinD1 (p = 0.002) amplification rates was observed between first and subsequent primary melanomas. Among the 107 patients with paired melanoma samples, 53 (49.5%) presented consistent alteration patterns between first and subsequent primary tumors. About one third (40/122; 32.8%) of subsequent melanomas presented a discrepant pattern of BRAF mutations as compared to incident primary tumors. Conclusions The low consistency in somatic mutation patterns among MPM lesions from same patients provides further evidence that melanomagenesis is heterogeneous and different cell types may be involved. This may have implications in clinical practice due to the difficulties in molecularly classifying patients with discrepant primary melanomas.
    Journal of Translational Medicine 05/2014; 12(1):117. DOI:10.1186/1479-5876-12-117 · 3.93 Impact Factor
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    • "There was a high incidence of melanoma-in-situ and only one thick melanoma of 9mm, a finding which does not support the suggestion that the MITF E318K mutation is associated with the development of a nodular subtype of melanoma (Ghiorzo et al., 2012), it is more in agreement with there being no association with Breslow thickness as reported in the Australian/UK study (Yokoyama et al., 2011). It is possible that greater surveillance of those at high risk of melanoma in Australia could explain these differences in that these cases of melanoma are more likely to be picked up early before progression to a nodular stage (Murali et al., 2012). "
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    ABSTRACT: A germline polymorphism of the MITF gene encoding a SUMOylation deficient E318K mutated protein has recently been described as a medium-penetrance melanoma gene. In a clinical assessment of nevi from 301 volunteers drawn from Queensland we identified 6 individuals as MITF E318K mutation carriers. The phenotype for 5 of these individuals showed a commonality of fair skin, body freckling varied over a wide range, with total nevi count between 46 to 430, all were multiple primary melanoma patients. The predominant dermoscopic signature pattern of nevi was reticular, the frequency of globular nevi in carriers varied and does not suggest that the MITF E318K mutation will be acting to force the continuous growth of nevi. Excised melanocytic lesions were available for 4 MITF E318K carrier patients and were compared to a matched range of WT melanocytic lesions. MITF staining pattern showed a predominant nuclear signal in all sections with no significant difference seen in nuclear/cytoplasmic ratio between mutation positive or negative samples. There was a high incidence of amelanotic melanomas found within the group, with 3 of the 5 melanomas from one patient suggesting a genetic interaction between the MITF E318K allele and an MC1R homozygous RHC variant genotype.Journal of Investigative Dermatology accepted article preview online, 17 June 2013; doi:10.1038/jid.2013.272.
    Journal of Investigative Dermatology 06/2013; 134(1). DOI:10.1038/jid.2013.272 · 7.22 Impact Factor
  • Journal of the American Academy of Dermatology 07/2012; 67(1):148-55. DOI:10.1016/j.jaad.2012.04.006 · 4.45 Impact Factor
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