Unclassified mesenchymal sarcoma with NTRK1-KHDRBS1 gene fusion: a case report of long-term tumor-free survival with crizotinib treatment

Abstract

Background Mesenchymal sarcomas are tumors that originate from mesenchymal tissue. Most mesenchymal sarcomas can be accurately classified, but some are unclassifiable in clinical practice. Molecular detection methods enable patients to benefit from molecular-targeted therapies for many cancers, including lung, breast, and bowel cancers. Further, even unclassified tumors can have therapeutic targets. NTRK gene fusions are sporadic genetic alterations that occur across tumor entities. If NTRK gene fusions are detected, TRK inhibitors can be used regardless of the tumor entity. Case presentation This report describes a case with an unclassifiable mesenchymal sarcoma carrying a neurotrophic tyrosine receptor kinase NTRK1-KHDRBS1 gene fusion that was diagnosed and treated at multiple hospitals. Diagnostic work-up included pathological and immunohistochemical analysis, which excluded angiosarcoma, dendritic cell sarcoma, and pseudomyogenic hemangioendothelioma. The patient achieved a long-term survival without tumor relapse after treatment with crizotinib. Conclusions This case will be of significant interest to pathologists because, despite the tumor being unclassified, a molecular target was identified. Although the FDA does not currently approve crizotinib for treatment of patients harboring NTRK gene fusions, this case provides new insights for diagnosis and treatment of mesenchymal sarcomas with NTRK1 gene translocations. Similar to ALKomas, which can be successfully treated using NTRK molecular-targeted therapy, tumors with NTRK gene translocations can be classified as NTRKomas, even when they occur at different organ sites, and with varying histological morphologies, and immunophenotypes.

Targeted Treatment of Soft-Tissue Sarcoma

“…In total, seven patients achieved CR, near CR, or NED. The patients achieving CR were treated as follows: Three patients received crizotinib targeting an NTRK1–KHDRBS1 fusion, ALK rearrangements, or an LMNA–NTRK1 fusion [ 32 , 33 , 34 ]; one patient received the MDM2 inhibitor, targeting an MDM2 amplification [ 11 ], and one patient received larotrectinib against a SPECC1L–NTRK3 fusion [ 35 ]. The two patients achieving NED received crizotinib against ALK expression and a SLC12A1–ROS1 fusion, respectively [ 36 ].…”

“…The patient with a near-CR response had an LMNA–NTRK1 fusion. The patients with NED had high ALK expression and a SLC12A1–ROS1 fusion [ 32 , 33 , 34 , 36 ].…”

Prevalence and clinico-genomic characteristics of patients with TRK fusion cancer in China

“…TRK inhibitors have attracted considerable attention in the past few years due to the dramatic, long-lasting response observed in patients with NTRK fusion who received therapy in early clinical trials 22 , 26 . Though multitargeted tyrosine kinase inhibitors such as crizotinib demonstrated efficacy in patients carrying the NTRK1 fusion 22 , 27 , 28 , selective TRK inhibitors revealed superior efficacy. Larotrectinib achieves a 78% objective response rate in tumors harboring NTRK fusion 4 , 6 , 29 , 30 , and it was approved by the FDA for the treatment of metastatic solid tumors carrying NTRK fusion, regardless of the underlying tumor histology 12 .…”