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often no higher than 10% (unpublished data, JP).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.