Microphthalmia transcription factor in malignant melanoma predicts occult sentinel lymph node metastases and survival

Abstract

Microphthalmia transcription factor (Mitf) is involved in melanocyte development and differentiation. We previously reported that Mitf expression, as detected by immunohistochemical analysis, is an independent prognostic marker in patients with intermediate-thickness melanoma. However, the clinical significance of Mitf expression in melanoma is not well delineated. In this prospective study, we attempted to demonstrate the correlation between Mitf expression in primary melanoma and the sentinel lymph node status and prognosis. We prospectively examined primary cutaneous melanomas from 94 patients undergoing nodal staging by sentinel lymph node biopsy. We quantified the percentage of tumor cells whose nuclei stained with the Mitf antibody visually. Survival curves were generated using the Kaplan-Meier method. The correlation between Mitf expression and nodal status was evaluated using the Mann-Whitney U-test. Here we demonstrate that Mitf expression is directly correlated with both disease-free survival (DFS) and overall survival (OS) over a median follow-up of 28.5 months. The mean DFS and OS in the eight patients whose melanomas did not stain positive for Mitf were 15.75±3.36 months (median, 12 months) and 38.17±5.18 months (median, 29 months), respectively. These results are significantly lower than those for patients who showed evidence of Mitf expression, in whom the mean DFS and OS were 66.1±4.03 months (median, not reached, P=0.0001) and 66.75±38.17 months (median, not reached, P=0.0001), respectively. The mean DFS and OS with greater than 25% (67 patients) of the melanoma cells staining positive for Mitf expression were 78.37±2.78 and 82.38±1.6 months, respectively, compared with 26.37±3.2 months (P=0.0001) and 44.53±4.5 months (P=0.0001), respectively, with up to 25% (27 patients) of cells stained positive for Mitf expression. In addition, there was a significant relationship between Mitf expression and nodal status, as evaluated by sentinel node biopsy. For example, none of the melanomas with greater than 50% Mitf expression had a positive sentinel node biopsy. Our study shows that expression of the molecular marker Mitf in primary cutaneous melanomas is a useful tool in assessing lymph node status. Mitf immunostaining in the primary tumor serves as a reliable predictor of occult lymph node metastases, as well as a favorable prognosticator of DFS and OS in melanoma patients.

Genetic alterations in main candidate genes during melanoma progression

“…For this reason the amplification of the MITF gene, with or without alterations of the corresponding protein expression levels, indicate patients who may benefit of treatment with inhibitors of histone deacetylase (HDAC), able to interfere with the expression of MITF protein [ 24 ]. To date, no predictive role for response to therapy has been documented, whereas MITF amplification has been implied on prediction of disease melanoma progression and disease prognosis [ 16 – 17 ].…”

“…Analogously, cKIT gene was found amplified in 2–7% of primary MCM, with higher amplification in metastatic than in primary lesions [ 13 ]. Moreover, the amplification of microphthalmia-associated transcription factor ( MITF ) gene seems to play a role in melanoma progression [ 16 , 17 ], while the role of the genomic amplification for EGFR and cMET genes is less clear [ 18 ]. Finally, little is known on the interactions between mutations and amplifications of such candidate genes into the initiation and progression of the MCM lesions.…”

Validation and Enhancement of the Clinicopathological Melanoma Nomogram via Incorporation of a Molecular Marker in the Primary Tumor

“…In a parallel effort, our group focused on the expression of MITF, a favorable molecular marker in cutaneous melanoma, in the primary tumors as a predictive factor of nodal involvement. Certainly, we showed that patients with higher MITF expression were less likely to have nodal spread (6). More specifically, we demonstrated in that report that none of the patients with MITF ≥50% had positive SLN.…”

“…Cytoplasmic staining was excluded from the analysis. MITF staining cut-off of ≥50% of the melanoma cells per slide (MITF≥50%) was used as an additional characteristic of the primary tumor based on our previous study (6).…”

“…Indeed, we were able to demonstrate that increased MITF expression in primary melanoma was associated with less aggressive phenotypes (3), decreased tumor growth (4), and improved overall and disease-free survival (5). Moreover, we recently showed that MITF expression in primary melanoma carries a predictive value for sentinel lymph node (SLN) metastasis (6).…”