Successful treatment of lipofibromatosis-like neural tumor of the lumbar spine with an NTRK-fusion inhibitor

Abstract

Background: Lipofibromatosis-like neural tumors (LPF-NT) are a newly identified class of rare mesenchymal neoplasms. Current standard of care therapy is surgical resection alone; there are no chemotherapies or molecular targeted therapies that have been shown to be effective in patients who are not surgical candidates due to either tumor bulk or location. Most LPF-NT harbor NTRK fusions, although the therapeutic significance of these fusions has not been previously demonstrated in this malignancy. Here, we present the first case of a patient with surgically-unresectable LPF-NT successfully treated with medical therapy, specifically the TRK fusion-protein inhibitor entrectinib. Case presentation: The patient is a 21 year old man with no co-morbidities who presented for evaluation due to intermittent abdominal pain and was found to have a mass spanning from T12-L2. Biopsy revealed a mesenchymal spindle cell neoplasm and S100 positivity pointed to possible nerve sheath origin. The sample was ultimately found to have an LMNA-NTRK1 fusion, confirming the diagnosis of LP-NFT. Unfortunately, due to the bulk and location of the tumor, surgery was felt to be exceptionally morbid and the patient was treated in a clinical trial with the NTRK inhibitor entrectinib. Surprisingly, he had such a robust clinical response that he was ultimately deemed a surgical candidate and he was successfully taken to surgery. Post-operative pathology revealed > 95% necrosis, demonstrating exceptional sensitivity to the targeted therapy. The patient remains NED and on entrectinib 12 months post-operatively. Conclusions: The exceptional treatment response of this patient suggests that NTRK fusions are true drivers of the disease. Thus, all patients should be evaluated for NTRK fusions using sensitive methodologies and treatment with TRK fusion-protein inhibitors should be considered in patients who are not candidates for oncologic resection.

NTRK‐rearranged spindle cell neoplasms are ubiquitous tumours of myofibroblastic lineage with a distinct methylation class

“…As illustrated here, targeted therapy (with crizotinib or entrectinib) may be an interesting alternative therapeutic option (for patients with unresectable or recurring tumours). 8,25 In summary, our study confirms that SCN-NTRK have a common myofibroblastic differentiation throughout the many affected organs and represent a new MC distinct from their differential histomolecular diagnoses, including IFS. Further series are needed to confirm these data and suggest a consensual nosology.…”

“…As per the last WHO classification of soft issue tumours, the lineage of SCN–NTRK remains unknown. Because of their S100 immunoexpression and spindle cell pattern, a potential neural differentiation was initially suggested 5,6,8,10,13–15,21,22,39 . In this study, we show that SCN–NTRK share a common DNA‐methylation profile known to be correlated with a distinct cell of origin.…”

“…This provisional category, included in the 2020 World Health Organisation (WHO) Classification of Soft Tissue Tumours, is associated with a wide morphological spectrum [IFS, IMT, lipofibromatosis‐like neural tumour and malignant peripheral nerve sheath tumour (MPNST)] 4 . SCN–NTRK harbour mainly NTRK1/2/3 gene fusions (75 reported cases to date) 5–17 . Alternative fusions (implicating ALK , BRAF , MET , RAF1 , RET and ROS1 genes) have also been reported, and their exact relationship to SCN–NTRK remains unknown 8,19–27 .…”

Update on Superficial Spindle Cell Mesenchymal Tumors in Children

“…This is true for DFSP, some non-resectable or relapsing cases of FHI, LPF-NT, and other tumors with gene fusions in NTRK, RAF, or RET. Although the presence of a gene fusion is not essential for malignancy, it is an important element of diagnostic information and may provide a rationale for treatment with RTK inhibitors (e.g., larotrectinib for NTRK-rearranged tumors, and anti-EGFR agents for FHI) [31,32].…”

Interstitial Deletions Generating Fusion Genes

“…The LMNA-NTRK1 codes for a chimeric tyrosine kinase. Patients with this fusion can be treated with kinase inhibitors such as crizotinib, entrectinib, and larotrectinib with significant clinical response (71,72,79,(81)(82)(83)(84)(85).…”