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. 2013 Sep;44(9):1902-11.
doi: 10.1016/j.humpath.2013.01.025. Epub 2013 May 9.

Oncogene abnormalities in a series of primary melanomas of the sinonasal tract: NRAS mutations and cyclin D1 amplification are more frequent than KIT or BRAF mutations

Meriem Chraybi  1 , Issam Abd Alsamad, Christiane Copie-Bergman, Maryse Baia, Jocelyne André, Nicolas Dumaz, Nicolas Ortonne
Affiliations

Oncogene abnormalities in a series of primary melanomas of the sinonasal tract: NRAS mutations and cyclin D1 amplification are more frequent than KIT or BRAF mutations

Meriem Chraybi et al. Hum Pathol. 2013 Sep.

Abstract

Primary malignant melanoma of sinonasal tract is a rare but severe form of melanoma. We retrospectively analyzed 17 cases and focused on the histologic presentation and the expression of c-Kit, epidermal growth factor receptor (EGFR), cyclin D1/Bcl-1, PS100, and HMB45 and searched for BRAF, NRAS, and KIT mutations that are known to be associated with melanoma subtypes, together with amplifications of KIT, cyclin D1, cyclin-dependent kinase 4, MDM2, and microphthalmia-associated transcription factor using quantitative polymerase chain reaction. In most cases (78%), an in situ component was evidenced. Invasive components were composed of diffuse areas of rhabdoid, epithelioid, or spindle cells and, in most cases, lacked inflammatory reaction, suggesting that an immune escape phenomenon probably develops when the disease progresses. EGFR was rarely and weakly expressed in the in situ component of 2 cases. None of the investigated case showed BRAF V600E, but 1 had a D594G mutation. NRAS mutations in exon 2 (G12D or G12A) were found in 3 cases (18%), and a KIT mutation in exon 11 (L576P), in 1, whereas c-Kit was expressed at the protein level in half of the cases. Amplifications of cyclin D1 were evidenced in 5 cases, confirmed in 3 by fluorescence in situ hybridization, but this was not always correlated with protein expression, found in 8 patients (62.5%), 3 having no significant amplification. In conclusion, primary malignant melanoma of sinonasal tract is not associated with BRAF V600E mutations. Instead, NRAS or KIT mutations and cyclin D1 amplification can be found in a proportion of cases, suggesting that primary malignant melanoma of sinonasal tract is heterogeneous at the molecular level and should not be sensitive to therapeutic approaches aiming at BRAF.

Keywords: BRAF mutation; CCND1 amplification; Cyclin D1; KIT; NRAS; Primary malignant melanoma of sinonasal tract; Sinonasal melanoma.

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Figures

Figure 1
Figure 1. Immunohistochemical results
A and B, Melan-A staining in case 17 shows a significant staining of neoplastic cells in both the in situ (A), and the invasive (B) components, with a strong and diffuse expression. The invasive components is mostly composed of sheets of spindle cells; C and D, C-Kit receptor is expressed in the majority of the neoplastic, morphologically undifferenciated cells in case 10, both by in situ (C) and invasive (D) cells; E and F, Representative cyclin-D1 immunostainings showing a strong nuclear expression by in situ and invasive components of case 17 (E) and 14 (F), respectively.
Figure 2
Figure 2. CCND1 FISH analysis using split signal FISH DNA probes
A high copy number of the CCND1 gene, with more than 10 signals per nuclei, can be evidenced in the majority (over 70% of cells) of neoplastic cells from cases 11 (A) and 4 (B).
Figure 3
Figure 3. Somatic mutations in sinonasal melanoma
Chromatograms showing the following mutated genes: KIT (A), BRAF (B), and NRAS (C, D). Sequences are shown above the chromatograms, arrows indicate the substitutions, the wild-type amino acids are in black and the mutated one in red.
See this image and copyright information in PMC

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