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.