Myxoid neoplasms with MAP3K kinase fusion: a study of 39 cases

Myxomas are benign soft tissue neoplasms typically driven by activating GNAS mutations. However, a subset lacks this alteration and remains molecularly undefined. Recent reports have implicated MAP3K family gene fusions in rare myxoid neoplasms sharing features with myxoma.

In this study, we characterise 39 MAP3K-rearranged myxoid tumours by integrating clinical, histopathological, immunohistochemical and molecular data. The cohort comprised predominantly middle-aged adults, with tumours distributed across a wide anatomic range (limbs, trunk, face), often in superficial locations. Histologically, the tumours were composed of bland spindle or histiocytoid cells embedded in an abundant myxoid stroma with features mimicking cellular myxoma, such as intermediate-to-high cellularity and broad fibrous septa. High-grade pleomorphism and necrosis were consistently absent. Immunohistochemistry revealed frequent CD34 and HMGA2 positivity, a low Ki-67 proliferation index, and preserved PRKAR1A expression. RNA sequencing identified diverse MAP3K gene fusions, most notably MSI2::MAP3K3 and MAP3K8::MAP3K3, alongside several unique fusion partners. Transcriptomic clustering demonstrated a relationship between MAP3K-rearranged tumours, GNAS-mutant myxomas and a proximity with myxofibrosarcomas, while clearly distinguishing them from other myxoid sarcomas. Clinical follow-up indicated an indolent course with no evidence of metastasis and rare local recurrences; notably, one patient with positive surgical margins remained disease-free several years postoperatively.

MAP3K-rearranged myxoid tumours represent a molecularly distinct subset of benign neoplasms that overlap histologically with cellular myxoma and must be distinguished from low-grade myxofibrosarcoma.