The patient is a 21-year-old young man without significant past medical history. He initially presented with a complaint of intermittent abdominal pain, and a CT scan revealed an abnormal paraspinal lesion. He underwent MRI which demonstrated the lesion extending from T12-L2 and measured 8.7 cm x 3.9 cm x 6.9 cm (Fig. 1a, b).
Subsequent biopsy revealed a spindle cell mesenchymal tumor with monotonous, bland spindle cells admixed with mature fat and occasional ectatic blood vessels (Fig. 2). Neither necrosis nor brisk mitotic activity were noted. IHC studies demonstrated positivity for CD34, pan-TRK, S-100 and SMA (not shown); the tumor was negative for Pankeratin cocktail, STAT6, DOG1, desmin, TLE1, panmelanocytic cocktail, and Sox10. Scattered cells labeled for SATB2 and H3K27me3. The tumor was negative for MDM2 amplification or FUS gene rearrangement using fluorescent in situ hybridization (FISH).
The S-100 staining raised the possibility of a peripheral nerve sheath origin. Given the pan-TRK immunoreactivity, the diagnosis of LPF-NT was considered; however, the site was unusual as it was not superficial. Thus, further molecular testing was performed. A custom-designed, clinically-validated anchored multiplex PCR-based targeted next-generation sequencing (NGS) RNA fusion panel that covers 485 exons from 81 genes and is optimized for formalin-fixed, paraffin-embedded (FFPE) samples, revealed a fusion between exon 2 of LMNA (NM_005572.3; chr1:156100564) and exon 11 of NTRK1 (NM_002529.3; chr1:156844698), predicted to encode an in-frame LMNA-NTRK1 fusion protein retaining the C-terminal kinase domain of NTRK1 (Fig. 3a). The fusion transcripts were confirmed with orthogonal RT-PCR and Sanger sequencing (Fig. 3b). Identification of this fusion reclassified the putative diagnosis to an S-100 positive LPF-NT of the spine.
Due to size and location, primary surgical resection would have been exceedingly morbid. Thus, the patient was entered into a phase II basket trial enrolling patients with NTRK 1/2/3, ROS1, or ALK gene rearrangements to be treated with entrectinib. He received a dose of 600 mg daily, and the only adverse effects were grade 1 diarrhea and taste alterations. Early response assessment after 1 month demonstrated a near-complete loss of enhancement and density of the mass, with the hounsfield units dropping from 200 on the initial scan to 55-60 at follow up (Figs. 1a, b, and 4). He had an excellent therapeutic response, with a 45% reduction in tumor size by RECIST criteria, measuring 4.0 x 2.8 cm (Fig. 5). Although the patient was not initially a surgical candidate due to unacceptable morbidity, his response to therapy was so exceptional that he ultimately qualified for surgical resection.
Therefore, he underwent vertebrectomy, which revealed a 7.0 x 5.2 x 3 cm mass with tan-white pink cut surface involving paraspinal soft tissue and protruding into the vertebral body, with underlying bony sclerosis. Histologically, there was extensive treatment response (> 95%) with decreased cellularity, marked hyalinization and focal areas of viable tumor cells (Fig. 6). The tumor focally involved soft tissue margins however bone margins were tumor-free. The patient has continued on entrectinib following surgery and remains without evidence of recurrence at 7 months.