A primary undifferentiated pleomorphic sarcoma of the lumbosacral region harboring a LMNA-NTRK1 gene fusion with durable clinical response to crizotinib: a case report

Abstract

BackgroundHigh-grade spindle cell sarcomas are a subtype of rare, undifferentiated pleomorphic sarcomas (UPSs) for which diagnosis is difficult and no specific treatment strategies have been established. The limited published data on UPSs suggest an aggressive clinical course, high rates of local recurrence and distant metastasis, and poor prognosis.Case presentationHere we present the unusual case of a 45-year-old male patient with a lumbosacral UPS extending into the sacrum. An initial diagnosis of a low-grade malignant spindle cell tumor was based on a tumor core biopsy. After complete extensive resection, the diagnosis of an UPS of the lumbosacral region was confirmed by excluding other types of cancers. Despite treatment with neoadjuvant radiotherapy, extensive resection, and adjuvant chemotherapy, the patient presented with multiple pulmonary metastases 3 months after surgery. The patient then began treatment with crizotinib at an oral dose of 450 mg per day, based on the detection of a LMNA-NTRK1 fusion gene in the tumor by next-generation sequencing. Over 18 months of follow-up through July 2018, the patient maintained a near-complete clinical response to crizotinib.ConclusionsThe LMNA-NTRK1 fusion was likely the molecular driver of tumorigenesis and metastasis in this patient, and the observed effectiveness of crizotinib treatment provides clinical validation of this molecular target. Molecular and cytogenetic evaluations are critical to accurate prognosis and treatment planning in cases of UPS, especially when treatment options are limited or otherwise exhausted. Molecularly targeted therapy of these rare but aggressive lesions represents a novel treatment option that may lead to fewer toxic side effects and better clinical outcomes.Electronic supplementary materialThe online version of this article (10.1186/s12885-018-4749-z) contains supplementary material, which is available to authorized users.

NTRK‐rearranged mesenchymal tumour in a 3‐year‐old female: a diagnostic quandary

“…They typically occur in children, adolescents and young adults, with rare reports in the third–fourth decade, and no gender predilection. These tumours may recur locally and have metastatic potential . Histologically, they are characterised by haphazardly arranged primitive cells in a myxoid background and/or spindle cells in long fascicles, often in conjunction with myopericytic/HPC‐like vessels, infiltrative growth, mxyoid appearance or inflammatory myofibroblastic areas, fairly brisk mitoses (3–4 HPF, with some cases up to 10–15 per 10 HPF), and CD34/S100 positivity.…”

“…Current first‐line therapy for paediatric patients with advanced solid tumours include cytotoxic chemotherapy, radiation therapy and sometimes disfiguring surgeries. Larotrectinib is an orally administered, highly selective small‐molecule TRK inhibitor with durable response rates and favourable toxicity profile …”

“…These tumours may recur locally and have metastatic potential. 1,3,5,6 Histologically, they are characterised by haphazardly arranged primitive cells in a myxoid background and/or spindle cells in long fascicles, often in conjunction with myopericytic/HPC-like vessels, infiltrative growth, mxyoid appearance or inflammatory myofibroblastic areas, fairly brisk mitoses (3-4 HPF, with some cases up to 10-15 per 10 HPF), and CD34/ S100 positivity. In addition to S100 positivity, the tumours often have areas with admixed mature adipose tissue; therefore, they were initially called lipofibromatosis-like neural tumours (LPF-NT).…”

“…Neurotrophic receptor tyrosine kinase genes, NTRK1 , NTRK2 and NTRK3 , encode the tropomyosin receptor kinases TRKA , TRKB and TRKC , respectively. Mesenchymal tumours, including low‐grade sarcomas harbouring NTRK gene fusions, are being increasingly described . We present a 3‐year‐old female with a diagnostically challenging skin and soft‐tissue tumour that clinically and immunohistochemically was a low‐grade spindle cell sarcoma mimicking dermatofibrosarcoma protuberans (DFSP).…”

“…Mesenchymal tumours, including low-grade sarcomas harbouring NTRK gene fusions, are being increasingly described. [1][2][3][4][5][6] We present a 3-year-old female with a diagnostically challenging skin and soft-tissue tumour that clinically and immunohistochemically was a low-grade spindle cell sarcoma mimicking dermatofibrosarcoma protuberans (DFSP). NTRK1 immunohistochemistry (IHC) and next-generation sequencing (NGS) confirmed the diagnosis of a NTRKrearranged mesenchymal tumour.…”