NTRK-rearranged spindle cell neoplasms (NTRK-RSCNs) are soft tissue tumors that harbor mainly NTRK1 or NTRK3 fusion genes, other than infantile fibrosarcoma (1). NTRK-RSCNs comprise a broad range of tumors, including morphological heterogeneity and histological grade. Histologically, NTRK-RSCNs resemble inflammatory myofibroblastic tumors, solitary fibrous tumors (SFTs), and malignant peripheral nerve sheath tumors (2,3). Recently, lipofibromatosis-like neural tumors were described, characterized by local aggressiveness and co-expression of Pan-TRK, CD34, and S100(4), which are involved in NTRK-RSCNs in the presence of the NTRK1 fusion gene. Regarding histological grade, NTRK-RSCNs range from benign to low- and high-grade lesions (1).

The frequency of NTRK-RSCNs is reported to be 0.68% in sarcoma cases, analyzing 1915 cases at Memorial Sloan Kettering Cancer Center (5). Assays commonly performed to identify NTRK fusions include Pan-TRK immunohistochemistry, fluorescence in situ hybridization, DNA sequencing using targeted cancer panels, and RNA sequencing. In clinical settings, Pan-TRK immunohistochemistry and DNA sequencing are commonly used; however, these assays can miss the detection of NTRK fusions at a frequency of approximately 20% (5). These methods tend to miss the detection of NTRK3 fusions, and the specificity and staining of Pan-TRK are reported to be low and faint in sarcoma cases (5). NTRK3 fusion-positive mesenchymal tumors are more aggressive than NTRK1 fusion-positive mesenchymal tumors (2). Therefore, the clinical features and characteristics of imaging findings are important to assess NTRK-RSCNs and treat patients with advanced NTRK-RSCNs, because NTRK inhibitors have shown dramatic and durable activity against NTRK fusion-positive tumors (6).

Several histopathological studies have focused on gene fusion and prognosis, but no previous case series has reported the radiological features of NTRK-RSCNs. Therefore, the present study aimed to clarify the radiological features of NTRK-RSCNs to improve the diagnostic rate of this rare tumor and compare them with histopathological features.

NTRK-RSCNs are extremely rare tumors, and identification of these tumors is important because NTRK inhibitors are highly effective and durable (6). NTRK-RSCNs include various fusion types, and their histological features and grades vary (1). According to a recent report, DNA-sequencing target panel and Pan-TRK immunohistochemistry, commonly available methods, could overlook these tumors (5); therefore, it is important to understand the clinical features of these tumors. There are only two case reports describing the imaging characteristics of these tumors (7,9). In this study, we characterized the MRI appearance of NTRK-RSCNs, which suggested that NTRK-RSCNs could be one of the differential diagnoses of highly vascular-rich mesenchymal tumors, such as SFT and alveolar soft part sarcoma (ASPS). Furthermore, we observed that NTRK-RSCNs can infiltrate the surrounding tissues, especially fat tissues, by comparing imaging characteristics and histopathological features. These findings could help surgeons plan the extent of resection of these tumors.

Imaging features of NTRK-RSCNs have been mentioned so far in only two case reports (7,9). This case series of six patients with NTRK-RSCNs reveals that these tumors have a highly vascular nature, presence of intra- or peritumoral vessels is characteristic feature of these tumors, and the findings are compatible with that of a previous case report (7,9). The number of flow voids and the diameter of flow-void vessels were different in each patient, and five out of the six patients showed intra- or peritumoral flow voids. As for other mesenchymal tumors with a highly vascular nature, SFTs and ASPS have been reported. McCarville et al reported that ASPS imaged with MRI in 19 patients had flow voids in all patients and that 95% (18/19 patients) of patients had both intra- and peripheral flow voids (10). Compared to the results of this report, NTRK-RSCNs could be less vascular than ASPS, although they tend to be highly vascular tumors. Crombé et al reported that ASPS had eight characteristic imaging features-deep location, high signal intensities on T1-weighted imaging, central area of necrosis, absence of fibrotic component, infiltrative growth pattern, absence of tail sign, presence of intra- and peritumoral flow voids, and number of flow voids ≥5. Moreover, 80% of ASPS pose at least seven out of the eight features (11). In our patients, the scores for these eight characteristics were 6, 7, 4, 3, 5, and 6 points in Cases 1-6, respectively. These results indicate that NTRK-RSCNs resemble ASPS in terms of highly vascular tumors, but NTRK-RSCNs tend to be less vascular than ASPS and have different imaging characteristics. SFT is an important differential diagnosis for NTRK-RSCNs because it shows monotonous spindle cell tumors and vascular-rich lesions with a hemangiopericytomatous appearance, which is also observed in NTRK-RSCNs (12). In our cases, three patients were first diagnosed with SFTs. Garcia-Bennett et al reported imaging findings of SFTs in nine patients and revealed that the common findings were well-defined polylobulated masses and the presence of vascular pedicles. However, invasion into adjacent structures was reported to be only 22% (13), and other reports of imaging findings of SFTs demonstrated that the ratio was 9% (14). In contrast, NTRK-RSCNs in our cases showed infiltration into the adjacent tissues on MRI, and infiltration into the surrounding tissues was confirmed by histopathological analysis. The finding of infiltration into adjacent tissues was consistent with previous reports (2,4,15). This infiltrative feature can be a differential point of imaging between SFTs and NTRK-RSCNs. SFT is histologically diagnosed using its specific molecular marker, STAT6, because of the NAB2-STAT6 fusion gene (16). In cases where imaging findings show a highly vascular mass and histological findings show spindle cell tumor without STAT6 immunostaining, the screening of NTRK gene fusion, including Pan-TRK, fluorescence in situ hybridization, DNA-sequencing targeted panel, and RNA sequencing, should be considered to discover NTRK-RSCNs. Recently, spindle cell tumors with CD34 or S100 immunostaining positive could pose other RTK-related fusions, including ALK, BRAF, ROS1, and RET (14,17). It is unknown whether these tumors are vascular-rich lesions; therefore, further investigation should be performed.

We recognized the clinically important feature, that is, focal infiltration of the tumor into adjacent structures, in imaging and histopathological findings, which was recently observed in previous case reports (7,9). In five of the six patients, infiltration into fatty tissue was observed on MRI, which was confirmed by histological findings. In Case 3, histological infiltration of the surrounding tissue, including fat tissue, intermuscular fat, and muscle, was observed despite imaging findings with the pushing type and no invasive pattern into fat tissue. This patient had metastasis after surgery, with relatively higher mitosis compared with other patients, and vascular invasion was observed histologically. Although it is difficult to conclude from our findings, due to limited cases, that imaging findings could not predict the malignant potential of this tumor, NTRK-RSCNs could have malignant potential although the imaging findings were well circumscribed. Furthermore, histological findings with high mitotic count should be considered a sign of malignant potential of this tumor, as described by previous reports (2,17), and vascular invasion should be carefully investigated, which could be a poor prognostic factor, similar to other soft tissue sarcomas (18). Intended wide resection with negative histological margins resulted in no recurrence in four patients, although one patient with a marginal margin had no recurrence. Considering the infiltrative nature of this tumor, wide resection is recommended. Effective chemotherapeutic NTRK inhibitors, including entrectinib and larotrectinib, are usually used in advanced cases, whereas the efficacy and safety of neoadjuvant larotrectinib treatment have been reported in the management of children with locally advanced TRK fusion sarcomas (19). To reduce the loss of function after extended tumor resection, neoadjuvant treatment with NTRK inhibitors for NTRK-RSCNs is promising, and further analysis is required.

The present study has some limitations. The has a retrospective design and analyzed a small number of patients. The entity of NTRK-RSCNs includes a broad range of histological features and grades, and local aggressiveness and metastatic potential differ depending on the tumor. However, our imaging findings of highly vascular tumors might be a common feature of this tumor driven by the same driver NTRK gene fusions. Despite these limitations, to the best of our knowledge, this is the first case series reporting the MRI findings of NTRK-RSCN lesions in soft tissues.

In conclusion, this study mainly presented two important imaging findings of NTRK-RSCNs-high vascularity and focal invasiveness into the surrounding tissues, especially fat tissue. NTRK-RSCNs could be candidates for the differential diagnosis of highly vascular mesenchymal tumors, including SFT and ASPS. Furthermore, the focal invasiveness of the tumor shown by MRI was confirmed by histopathological analysis, and NTRK-RSCNs could be resected with wide margin to avoid local recurrence. These findings provide useful information for the diagnosis and treatment of NTRK-RSCNs and would aid in improving the detection and curative rates of these tumors.