Discussion
Novel ERC1::ALK fusion sarcoma can be successfully treated with oral crizotinib, in this case sparing distal forearm amputation in a pediatric patient.
The oncogenesis of ALK -fusion-positive sarcomas involves promoter interruption with subsequent dysregulated tyrosine-kinase activity. In non-mesenchymal tumors, the discovery of ALK mutations in 3–5% of patients with non-small cell lung cancer (NSCLC)4,5drove early-phase clinical studies of crizotinib, a first-in-class dualALK/MET/ ROS1 small molecular tyrosine-kinase inhibitor6,7 with good oral bioavailability that targets ATP-induced catalytic capacity of ALK kinases, inducing apoptosis of tumor cells at the G1-S phase checkpoint8. The dramatic response rates in NSCLC validated ALK as a therapeutic target and led to expedited FDA approval of crizotinib in August 2011 for use in patients with ALK-rearranged lung cancer9,10.
Use of targeted therapy for ALK fusion sarcoma/mesenchymal tumors including inflammatory myofibroblastic tumor has been demonstrated11 and is still being described with some of the newer fusions. The tyrosine-kinase RAS::MAPK pathway fusion sarcomas include NTRK, BRAF, RAF1, RET, FGFR1 and ABL1 are still evolving. These pathway sarcomas were first noted as infantile fibrosarcoma in infants with an ETV6:NTRK3fusion12. An identical fusion was subsequently noted in morphologically similar congenital mesoblastic nephroma13. In addition to other NTRK1, NTRK2 and NTRK3 fusions, these have been reported as an emerging entity ofNTRK -rearranged spindle cell neoplasm in the latest World Health Organization (WHO) Bone and Soft Tissue Tumours Classification14. Most of these tumors appear low-grade with myopericytic spindled to ovoid cells that infiltrate into muscle and fat in a lipofibromatosis-like pattern1,2,15. These low-grade fusion sarcomas often have focal CD34 and/or S100 protein and are negative for SOX1016,17 excluding the possibility of a nerve sheath tumor. A second fusion-sarcoma morphology of a high-grade spindled pleomorphic tumor has been reported, observed only with certain NTRK fusion partners including TPR and KANK11. These tumors can be superficial dermal and subcutaneous18 or deep and intramuscular/intraosseous1,19. While the low-grade behavior of these ovoid-spindled tumors generally allow for complete surgical excision, those with deep involvement, metastasis, or in our case the interdigitating infiltration of the tumor that would have required a distal forearm amputation, are best treated with crizotinib. The correct decision to pursue single agent monotherapy may guide future management if non-resectable and medical agents aimed at molecular targets demonstrates promise in reducing long-term morbidity. Serious adverse events include cytopenias, visual disturbances, and gastrointestinal upset, which may result in skipped doses or dose reduction, as in our patient.
Novel ALK-fusion sarcomas may respond to molecular-targeting agents, such as crizotinib and next-generation ALK-inhibitors. In particular, the ERC1::ALK fusion sarcoma in our patient representing aRAS::MAPK tyrosine-kinase pathway tumor, was targeted and treated successfully by a single oral agent, crizotinib, precluding amputation and resulting in complete radiographic and clinical remission.