Fig. 3

RAS/MAPK pathway alterations in histiocytic sarcoma and response to targeted therapy in a patient with NF1-mutated histiocytic sarcoma. a Summary of activating mutations involving the RAS/MAPK signaling pathway. b Schematic showing coding mutations of the most frequently mutated genes of the RAS/MAPK signaling pathway including a TPM3-NTRK1 fusion between exons 1–7 of TPM3 (coiled-coil domain) and exons 12–17 of NTRK1 (includes the kinase domain). c Clinical timeline of events with corresponding imaging, histopathologic, and molecular findings. (i) Baseline coronal FDG-PET/CT showing intensely FDG-avid retroperitoneal and mesenteric lymphadenopathy (arrows). Biopsy of the mesenteric lymph node showed sheets of large atypical histiocytoid cells (Hematoxylin & Eosin stain, ×400 magnification) with highly pleomorphic forms and giant cells. A NF1-truncating mutation was identified at diagnosis (p.C1032Lfs*7), which would result in loss of the major catalytic GAP-related domain (GRD) (schematic below images), (ii) Partial metabolic response after three cycles of cobimetinib with residual FDG-avid mesenteric lymph nodes (arrows), (iii) Disease progression after five cycles with increased mesenteric and retroperitoneal adenopathy (lower arrows) as well as new FDG-avid supraclavicular and mediastinal adenopathy (upper arrows). A biopsy of the same mesenteric lymph node at disease progression showed slightly decreased tumor cellularity with stromal hyalinization (×400 magnification). There was also dramatic reduction in phosphorylated ERK expression on cobimetinib therapy consistent with drug-mediated MEK inhibition (×400 magnification); however, there was persistent expression of phosphorylated S6 protein (data not shown). This was also associated with the acquisition of a CBL RING domain mutation (p.C396R) (schematic below images). d Table showing mutations and respective allele fractions at diagnosis and at disease progression following therapy