RESUMO
AIMS: This study was performed to elucidate the clinicopathological characteristics, genetic alterations and therapeutic targets of primary malignant melanoma of the oesophagus (PMME). METHODS AND RESULTS: The clinicopathology and molecular pathology of 13 PMME cases and 10 skin malignant melanoma (SKMM) cases were analysed with next-generation sequencing (NGS) and immunohistochemistry. The 3-year overall survival rate and the median survival time for PMME patients were 23.1% and 11.9 months, respectively. Three (23.1%) and eight (61.5%) PMME cases showed a papillary structure and lymph node metastasis, respectively. DNA and RNA hybridization capture-based NGS analysis revealed that NF1 was the most frequently mutated gene (30%) in 10 of the PMME cases. Other mutations detected in PMME included SF3B1 (20%), KRAS (10%), BRCA2 (10%), KIT (10%) and TP53 (10%) mutations. Commonly detected BRAF mutations in SKMM were not detected in PMME. Immunohistochemistry and mutation status were concordant between p53/c-Kit and TP53/KIT, respectively. Focal expression of programmed death-ligand 1 was observed in one PMME sample. The tumour mutation burden in PMME was significantly lower than that in SKMM (P = 0.030). No PMME case showed high microsatellite instability. RNA sequencing revealed a distinctive pattern with respect to RNA expression. T-cell co-stimulation differed between PMME and SKMM. CONCLUSIONS: The RAS-mitogen-activated protein kinase pathway is one of the main pathways involved in PMME. The genetic profile of PMME was similar to that of mucosal/acral melanoma, but differed from the SKMM profile. A subset of PMMEs may contain actionable mutations. Immunotherapy seemed to be less effective for most PMMEs in this series.