Comprehensive clinicopathological and molecular analysis of primary malignant melanoma of the oesophagus

AIMS This study was performed to elucidate the clinicopathological characteristics, genetic alterations, and therapeutic targets of primary malignant melanoma of the oesophagus (PMME). METHODS The clinicopathology and molecular pathology of 13 PMME and 10 skin malignant melanoma (SKMM) cases were analysed via next-generation sequencing (NGS) and immunohistochemistry. RESULTS Three-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 exhibited a papillary structure and lymph node metastasis, respectively. DNA and RNA hybridisation 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%). 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 PD-L1 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 displayed 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-MAPK 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 PMME may contain actionable mutations. Immunotherapy seemed to be less effective for most PMMEs in this series.