depleted of both of them (Figure C). NNK-SMZL expressed significantly higher levels of genes belonging to NOTCH2 pathway and of genes that are activated by non-canonical NF-κB transcription factors. Conversely, DMT-SMZL had a signature of TP53 and apoptosis impairment (Figure D). Digital cytometry and in situ profiling segregated two basic types of SMZL immune microenvironment termed inflamed SMZL (50% of cases, associated with inflammatory cells and immune checkpoint activation) and noninflamed SMZL (50% of cases) (Figure E and F). The combination of molecular and phenotypic profiling allowed to sort out a high risk clinical subset of patients whose tumor was characterized by having both NNK genotype and ''inflamed'' microenvironment (Figure G). Conclusions: Our study highlights the complexity of SMZL. The molecular framework provides an evolving understanding of the pathogenesis of SMZL, and can be regarded as a building block for further refining the classification of B-cell tumors of the spleen, and for aiding the development of rationally targeted treatments.

The treatment of BRAFV600E mutant melanoma has been revolutionized by BRAF inhibitors. Furthermore, the BRAF/MEK combination has shown further improvement in clinical outcomes in advanced and in adjuvant melanoma patients. In low-grade ovarian tumors, BRAF inhibitor use has been also proposed. Here we present a patient with an excellent, lasting response to BRAF therapy alone. At first progression, after more than two years on BRAF monotherapy, we could not identify any molecular mechanisms explaining resistance. After a switch to dual BRAF/MEK therapy, the patient responded. However, despite the initial response clinical the patient again progressed, this time with the appearance of a KRAS G12C mutation, which could not be overcome by BRAF/MEK therapy. We provide evidence that BRAF inhibitor alone can be highly beneficial in BRAF mutant low-grade ovarian tumors and the resistance mechanisms are similar to that of other BRAF mutant tumors, including in melanoma.