Discussion
Our findings highlight the unique and differential biology hijacked by select BRAF fusions, which impacts RAFi responsiveness. Though functional data predicts similar effects for these two novel fusions, each of these histiocytic neoplasms had a discordant clinical to pathologic behavior. Typical JXG family lesions often show indolent behavior in pediatric patients19. Even in rare systemic presentations, they do not typically feature a lymphatic-type dissemination, as demonstrated in case 2. Furthermore, Ki-67 proliferation index in JXG lesions is typically less than 20%, and more often no higher than 10% (unpublished data, JP). The focally high proliferation rate (up to 40%) in this MS4A6A-BRAF JXG family lesion appeared to correlate with its aggressive clinical presentation, despite its seemingly low-grade morphology. On the contrary, malignant histiocytic neoplasms lesions typically have aggressive clinical behavior18, unlike case 1, which after surgical excision had an indolent course.
The MTAP-BRAF malignant histiocytic neoplasm had only modestly elevated proliferation rate (up to 20%), which is lower than most malignant histiocytic neoplasms (often >30%)20. Thus, the lower Ki-67 proliferation rate, also appeared to correlate with its indolent behavior, despite its high-grade morphology. Both of these unusual, divergent phenotypes further emphasize that in histiocytic neoplasms, the integration of histopathologic, molecular, and clinical/radiographic data are required to obtain a comprehensive assessment of clinical aggressiveness and nominate rational treatment options. A detailed mechanistic classification of BRAF fusions that predict responsiveness to targeted agents is warranted.