| Tumor type . | Clinical features . | |
|---|---|---|
| Infantile fibrosarcoma (IFS) | IFS with canonical ETV6-NTRK3 fusions | Histological features: Interlacing fascicles of spindle cells with focal necrosis, mitoses, and a focal hemangiopericytomatous vascular pattern [33]. Clinically and pathologically, they may mimic vascular/lymphatic malformations [34] Immunohistochemical features: Most cases are positive for vimentin [33] and pan-TRK immunostaining [35] Genetic features: ETV6-NTRK3 [13] Radiological features: CT/MRI shows aberrant vascularization pattern, necrosis, and hemorrhage [27] Prognosis: Generally favorable, better prognosis compared to adult-type fibrosarcoma [36] Differential diagnosis: Vascular/lymphatic malformations [34], infantile myofibromatosis [37] TRK inhibitor: Larotrectinib has shown a 96% response rate (27/28) for IFS [16] |
| IFS-like lesions with related fusion kinases (IFS-like tumors) | Histological features: Monomorphic spindle cells arranged in long, intersecting fascicles [30] Immunohistochemical features: These tumors demonstrated a heterogeneous immunoprofile. While no single marker was consistently expressed across all cases, variable positivity was observed for CD34, S100, smooth muscle actin (SMA), and CD30 [38] Genetic features: A number of fusion genes have been identified, including EML4-NTRK3 [39] and LMNA-NTRK1 [40], BRAF [41], and MET [42] Radiological features: It is possible for tumors to infiltrate adjacent structures [42] Prognosis: These tumors exhibited locally aggressive behavior [38]. Metastases were rare, with lung metastases reported in 1 of 6 cases [38] Differential diagnosis: N.A. TRK inhibitor: One patient showed partial response to lartrectinib with a 93% reduction [43], all three patients with IFS with NTRK1 fusions responded to larotrectinib [16]. One IFS (case 15) with a SPECC1L-NTRK3 fusion was treated with larotrectinib and achieved complete tumor regression [44] | |
| Neurotrophic receptor tyrosine kinase (NTRK)-rearranged spindle cell neoplasm | Lipofibromatosis-like neural tumor (LPF-NT) | Histological features: Spindle-shaped cell tumors with a notably infiltrative growth pattern have been observed in the superficial soft tissues of children and young adults [24,45] Immunohistochemical features: Co-express S100 and CD34 [24,45] Genetic features: The NTRK1 fusion gene is associated [24,45] Radiological features: LPF-LT lesions are frequently characterized as relatively well-defined masses primarily involving subcutaneous tissues, with some cases exhibiting diffuse thickening and minimal extension into deeper soft tissues [46–48] In one reported case, magnetic resonance imaging (MRI) findings included areas of T2 hyperintensity, intermediate T1 signal intensity, and occasional small fat components [46] Prognosis: LPF-LT is predominantly a benign or locally aggressive neoplasm with rarely metastases or disease-related mortality reported in typical cases [24] Differential diagnosis: Lipofibromatosis and low-grade MPNSTs [30] TRK inhibitor: One patient with LPF-NT who had difficulty in primary surgical resection took preoperative entrectinib, and 45% reduction of tumor lead to tumor resection [48] |
| Spindle cell tumors with S100 and CD34 co-reactivity resembling malignant peripheral nerve sheath tumor (MPNST) | Histological features: They resemble MPNSTs but with keloid-like collagen around connective tissue and vessels [25,30]. These tumors show low cellularity, a low mitotic count, and lacked necrosis, although some cases demonstrate a malignant phenotype [25] Immunohistochemical features: Often co-expresses S100 and CD34 [25] Genetic features: Often with NTRK1/2, RAF1 or BRAF fusion genes [25] Radiological features: N.A. Prognosis: Hypocellular tumors are classified as low grade, exhibit a favorable prognosis, and show slow cell growth [25]. However, if the tumor shows increased cell density and mitotic activity, there is an increased likelihood of distant metastasis [25] Differential diagnosis: Low-grade or intermediate-grade MPNSTs [25] TRK inhibitor: Sixteen out of 30 patients (53%) with soft tissue sarcoma (STS), including 6 MPNST, responded to larotrectinib [49] | |
| Adult-type fibrosarcoma | Histological features: The histology shows sweeping fascicles of spindle cells that may exhibit storiform architecture, herringbone patterns, hemangiopericytomatous vessels, and mild nuclear atypia in some cases [23,50] Immunohistochemical features: CD34 immunostaining was positive in the majority of cases, whereas S100 was negative, and pan-TRK immunostaining was positive in many cases [23,50] Genetic features: It may be associated with NTRK3 [23,50] fusion genes Radiological features: N.A. Prognosis: The prognosis varies widely, from low to high malignancy [23,50] Differential diagnosis: Differential diagnoses include MPNST, fibrosarcomatous dermatofibrosarcoma protuberans, solitary fibrous tumor, and synovial sarcoma [23] TRK inhibitor: Sixteen out of 30 patients (53%) with soft tissue sarcoma (STS), including 1 adult-type fibrosarcoma, responded to larotrectinib [49] | |
| Spindle cell sarcomas with hemangiopericytic or myopericytoma-like pattern | Histological features: Histologically, the tumor exhibits a growth pattern similar to hemangiopericytoma or myopericytoma, often with high mitotic activity [22] Immunohistochemical features: Immunohistochemically, some cases of SMA and CD34 positivity were observed [22] Genetic features: It is associated with the NTRK1 fusion gene [22] Radiological features: Typical MRI characteristics include isointensity on T1-weighted images, high signal intensity on T2-weighted images, intense contrast enhancement, and the absence of fatty components or lobular architecture [28] Prognosis: Low-grade sarcomas with myopericytoma or hemangiopericytoma-like morphology often exhibit a more favorable prognosis, though some cases may show aggressive behavior [22,28] Differential diagnosis: Myopericytoma and hemangiopericytoma, solitary fibrous tumor, IFS, myofibromatosis [22] TRK inhibitor: Sixteen out of 30 patients (53%) with soft tissue sarcoma (STS), including two with myopericytoma, responded to larotrectinib [49] | |
| Inflammatory myofibroblastic tumors (IMTs) harboring fusions involving ALK and other kinases | Histological features: Histological features are highly diverse, ranging from inflammatory pseudotumors with few spindle cells and prominent inflammation to highly cellular myofibroblastic proliferations or sarcomatous neoplasms lacking significant inflammation or fibromyxoid stroma [51] Immunohistochemical features: Immunohistochemically, several cases showed positive staining for ALK or ROS1 [51] Genetic features: Cases of IMT with ALK gene rearrangement, ROS1 [51], RET [51] rearrangement, and ETV6-NTRK3 fusion [52,53] have been reported Radiological features: IMTs typically appear as homogeneous or heterogeneous lesions with variable enhancement on contrast-enhanced computed tomography or gadolinium-enhanced MRI, reflecting fibrotic tissue. T1- and T2-weighted MRI sequences often show low signal intensity due to the tumor’s fibrotic composition [54] Prognosis: Three out of four cases reported in two studies have maintained long-term disease-free survival [52,53] Differential Diagnosis: Rhabdomyosarcoma, fibrosarcoma, synovial sarcoma [53,54] TRK inhibitor: Sixteen out of 30 patients (53%) with soft tissue sarcoma (STS), including two with IMT, responded to entrectinib [49] | |
| Spindle cell/sclerosing rhabdomyosarcoma (ssRMS) | Histological features: ssRMS exhibits three histological patterns—fibrosarcoma-like, VGLL2-type, and Triton-like—characterized by fibromatous-like appearance with sparse tumor cells in abundant sclerotic stroma, moderate atypia, and rare mitotic figures [55] Immunohistochemical features: Heterogeneous staining with desmin, myogenin [55] Genetic features: TPM3-NTRK1, SYPL1-BRAF, and TOP2B-RAF1 have been reported [55] Radiological features: The ssRMS show slightly high intensity on T2-weighted and iso- or high intensity on T1-weighted images compared to muscle. On post-contrast images, ssRMS showed hetero- or homogeneous enhancement, as described in a case report [56] Prognosis: Fusion-positive ssRMS has a very good outcome [55] Differential diagnosis: N.A. TRK inhibitor: N.A. | |
| Tumor type . | Clinical features . | |
|---|---|---|
| Infantile fibrosarcoma (IFS) | IFS with canonical ETV6-NTRK3 fusions | Histological features: Interlacing fascicles of spindle cells with focal necrosis, mitoses, and a focal hemangiopericytomatous vascular pattern [33]. Clinically and pathologically, they may mimic vascular/lymphatic malformations [34] Immunohistochemical features: Most cases are positive for vimentin [33] and pan-TRK immunostaining [35] Genetic features: ETV6-NTRK3 [13] Radiological features: CT/MRI shows aberrant vascularization pattern, necrosis, and hemorrhage [27] Prognosis: Generally favorable, better prognosis compared to adult-type fibrosarcoma [36] Differential diagnosis: Vascular/lymphatic malformations [34], infantile myofibromatosis [37] TRK inhibitor: Larotrectinib has shown a 96% response rate (27/28) for IFS [16] |
| IFS-like lesions with related fusion kinases (IFS-like tumors) | Histological features: Monomorphic spindle cells arranged in long, intersecting fascicles [30] Immunohistochemical features: These tumors demonstrated a heterogeneous immunoprofile. While no single marker was consistently expressed across all cases, variable positivity was observed for CD34, S100, smooth muscle actin (SMA), and CD30 [38] Genetic features: A number of fusion genes have been identified, including EML4-NTRK3 [39] and LMNA-NTRK1 [40], BRAF [41], and MET [42] Radiological features: It is possible for tumors to infiltrate adjacent structures [42] Prognosis: These tumors exhibited locally aggressive behavior [38]. Metastases were rare, with lung metastases reported in 1 of 6 cases [38] Differential diagnosis: N.A. TRK inhibitor: One patient showed partial response to lartrectinib with a 93% reduction [43], all three patients with IFS with NTRK1 fusions responded to larotrectinib [16]. One IFS (case 15) with a SPECC1L-NTRK3 fusion was treated with larotrectinib and achieved complete tumor regression [44] | |
| Neurotrophic receptor tyrosine kinase (NTRK)-rearranged spindle cell neoplasm | Lipofibromatosis-like neural tumor (LPF-NT) | Histological features: Spindle-shaped cell tumors with a notably infiltrative growth pattern have been observed in the superficial soft tissues of children and young adults [24,45] Immunohistochemical features: Co-express S100 and CD34 [24,45] Genetic features: The NTRK1 fusion gene is associated [24,45] Radiological features: LPF-LT lesions are frequently characterized as relatively well-defined masses primarily involving subcutaneous tissues, with some cases exhibiting diffuse thickening and minimal extension into deeper soft tissues [46–48] In one reported case, magnetic resonance imaging (MRI) findings included areas of T2 hyperintensity, intermediate T1 signal intensity, and occasional small fat components [46] Prognosis: LPF-LT is predominantly a benign or locally aggressive neoplasm with rarely metastases or disease-related mortality reported in typical cases [24] Differential diagnosis: Lipofibromatosis and low-grade MPNSTs [30] TRK inhibitor: One patient with LPF-NT who had difficulty in primary surgical resection took preoperative entrectinib, and 45% reduction of tumor lead to tumor resection [48] |
| Spindle cell tumors with S100 and CD34 co-reactivity resembling malignant peripheral nerve sheath tumor (MPNST) | Histological features: They resemble MPNSTs but with keloid-like collagen around connective tissue and vessels [25,30]. These tumors show low cellularity, a low mitotic count, and lacked necrosis, although some cases demonstrate a malignant phenotype [25] Immunohistochemical features: Often co-expresses S100 and CD34 [25] Genetic features: Often with NTRK1/2, RAF1 or BRAF fusion genes [25] Radiological features: N.A. Prognosis: Hypocellular tumors are classified as low grade, exhibit a favorable prognosis, and show slow cell growth [25]. However, if the tumor shows increased cell density and mitotic activity, there is an increased likelihood of distant metastasis [25] Differential diagnosis: Low-grade or intermediate-grade MPNSTs [25] TRK inhibitor: Sixteen out of 30 patients (53%) with soft tissue sarcoma (STS), including 6 MPNST, responded to larotrectinib [49] | |
| Adult-type fibrosarcoma | Histological features: The histology shows sweeping fascicles of spindle cells that may exhibit storiform architecture, herringbone patterns, hemangiopericytomatous vessels, and mild nuclear atypia in some cases [23,50] Immunohistochemical features: CD34 immunostaining was positive in the majority of cases, whereas S100 was negative, and pan-TRK immunostaining was positive in many cases [23,50] Genetic features: It may be associated with NTRK3 [23,50] fusion genes Radiological features: N.A. Prognosis: The prognosis varies widely, from low to high malignancy [23,50] Differential diagnosis: Differential diagnoses include MPNST, fibrosarcomatous dermatofibrosarcoma protuberans, solitary fibrous tumor, and synovial sarcoma [23] TRK inhibitor: Sixteen out of 30 patients (53%) with soft tissue sarcoma (STS), including 1 adult-type fibrosarcoma, responded to larotrectinib [49] | |
| Spindle cell sarcomas with hemangiopericytic or myopericytoma-like pattern | Histological features: Histologically, the tumor exhibits a growth pattern similar to hemangiopericytoma or myopericytoma, often with high mitotic activity [22] Immunohistochemical features: Immunohistochemically, some cases of SMA and CD34 positivity were observed [22] Genetic features: It is associated with the NTRK1 fusion gene [22] Radiological features: Typical MRI characteristics include isointensity on T1-weighted images, high signal intensity on T2-weighted images, intense contrast enhancement, and the absence of fatty components or lobular architecture [28] Prognosis: Low-grade sarcomas with myopericytoma or hemangiopericytoma-like morphology often exhibit a more favorable prognosis, though some cases may show aggressive behavior [22,28] Differential diagnosis: Myopericytoma and hemangiopericytoma, solitary fibrous tumor, IFS, myofibromatosis [22] TRK inhibitor: Sixteen out of 30 patients (53%) with soft tissue sarcoma (STS), including two with myopericytoma, responded to larotrectinib [49] | |
| Inflammatory myofibroblastic tumors (IMTs) harboring fusions involving ALK and other kinases | Histological features: Histological features are highly diverse, ranging from inflammatory pseudotumors with few spindle cells and prominent inflammation to highly cellular myofibroblastic proliferations or sarcomatous neoplasms lacking significant inflammation or fibromyxoid stroma [51] Immunohistochemical features: Immunohistochemically, several cases showed positive staining for ALK or ROS1 [51] Genetic features: Cases of IMT with ALK gene rearrangement, ROS1 [51], RET [51] rearrangement, and ETV6-NTRK3 fusion [52,53] have been reported Radiological features: IMTs typically appear as homogeneous or heterogeneous lesions with variable enhancement on contrast-enhanced computed tomography or gadolinium-enhanced MRI, reflecting fibrotic tissue. T1- and T2-weighted MRI sequences often show low signal intensity due to the tumor’s fibrotic composition [54] Prognosis: Three out of four cases reported in two studies have maintained long-term disease-free survival [52,53] Differential Diagnosis: Rhabdomyosarcoma, fibrosarcoma, synovial sarcoma [53,54] TRK inhibitor: Sixteen out of 30 patients (53%) with soft tissue sarcoma (STS), including two with IMT, responded to entrectinib [49] | |
| Spindle cell/sclerosing rhabdomyosarcoma (ssRMS) | Histological features: ssRMS exhibits three histological patterns—fibrosarcoma-like, VGLL2-type, and Triton-like—characterized by fibromatous-like appearance with sparse tumor cells in abundant sclerotic stroma, moderate atypia, and rare mitotic figures [55] Immunohistochemical features: Heterogeneous staining with desmin, myogenin [55] Genetic features: TPM3-NTRK1, SYPL1-BRAF, and TOP2B-RAF1 have been reported [55] Radiological features: The ssRMS show slightly high intensity on T2-weighted and iso- or high intensity on T1-weighted images compared to muscle. On post-contrast images, ssRMS showed hetero- or homogeneous enhancement, as described in a case report [56] Prognosis: Fusion-positive ssRMS has a very good outcome [55] Differential diagnosis: N.A. TRK inhibitor: N.A. | |
Abbreviation: N.A., not available.
| Tumor type . | Clinical features . | |
|---|---|---|
| Infantile fibrosarcoma (IFS) | IFS with canonical ETV6-NTRK3 fusions | Histological features: Interlacing fascicles of spindle cells with focal necrosis, mitoses, and a focal hemangiopericytomatous vascular pattern [33]. Clinically and pathologically, they may mimic vascular/lymphatic malformations [34] Immunohistochemical features: Most cases are positive for vimentin [33] and pan-TRK immunostaining [35] Genetic features: ETV6-NTRK3 [13] Radiological features: CT/MRI shows aberrant vascularization pattern, necrosis, and hemorrhage [27] Prognosis: Generally favorable, better prognosis compared to adult-type fibrosarcoma [36] Differential diagnosis: Vascular/lymphatic malformations [34], infantile myofibromatosis [37] TRK inhibitor: Larotrectinib has shown a 96% response rate (27/28) for IFS [16] |
| IFS-like lesions with related fusion kinases (IFS-like tumors) | Histological features: Monomorphic spindle cells arranged in long, intersecting fascicles [30] Immunohistochemical features: These tumors demonstrated a heterogeneous immunoprofile. While no single marker was consistently expressed across all cases, variable positivity was observed for CD34, S100, smooth muscle actin (SMA), and CD30 [38] Genetic features: A number of fusion genes have been identified, including EML4-NTRK3 [39] and LMNA-NTRK1 [40], BRAF [41], and MET [42] Radiological features: It is possible for tumors to infiltrate adjacent structures [42] Prognosis: These tumors exhibited locally aggressive behavior [38]. Metastases were rare, with lung metastases reported in 1 of 6 cases [38] Differential diagnosis: N.A. TRK inhibitor: One patient showed partial response to lartrectinib with a 93% reduction [43], all three patients with IFS with NTRK1 fusions responded to larotrectinib [16]. One IFS (case 15) with a SPECC1L-NTRK3 fusion was treated with larotrectinib and achieved complete tumor regression [44] | |
| Neurotrophic receptor tyrosine kinase (NTRK)-rearranged spindle cell neoplasm | Lipofibromatosis-like neural tumor (LPF-NT) | Histological features: Spindle-shaped cell tumors with a notably infiltrative growth pattern have been observed in the superficial soft tissues of children and young adults [24,45] Immunohistochemical features: Co-express S100 and CD34 [24,45] Genetic features: The NTRK1 fusion gene is associated [24,45] Radiological features: LPF-LT lesions are frequently characterized as relatively well-defined masses primarily involving subcutaneous tissues, with some cases exhibiting diffuse thickening and minimal extension into deeper soft tissues [46–48] In one reported case, magnetic resonance imaging (MRI) findings included areas of T2 hyperintensity, intermediate T1 signal intensity, and occasional small fat components [46] Prognosis: LPF-LT is predominantly a benign or locally aggressive neoplasm with rarely metastases or disease-related mortality reported in typical cases [24] Differential diagnosis: Lipofibromatosis and low-grade MPNSTs [30] TRK inhibitor: One patient with LPF-NT who had difficulty in primary surgical resection took preoperative entrectinib, and 45% reduction of tumor lead to tumor resection [48] |
| Spindle cell tumors with S100 and CD34 co-reactivity resembling malignant peripheral nerve sheath tumor (MPNST) | Histological features: They resemble MPNSTs but with keloid-like collagen around connective tissue and vessels [25,30]. These tumors show low cellularity, a low mitotic count, and lacked necrosis, although some cases demonstrate a malignant phenotype [25] Immunohistochemical features: Often co-expresses S100 and CD34 [25] Genetic features: Often with NTRK1/2, RAF1 or BRAF fusion genes [25] Radiological features: N.A. Prognosis: Hypocellular tumors are classified as low grade, exhibit a favorable prognosis, and show slow cell growth [25]. However, if the tumor shows increased cell density and mitotic activity, there is an increased likelihood of distant metastasis [25] Differential diagnosis: Low-grade or intermediate-grade MPNSTs [25] TRK inhibitor: Sixteen out of 30 patients (53%) with soft tissue sarcoma (STS), including 6 MPNST, responded to larotrectinib [49] | |
| Adult-type fibrosarcoma | Histological features: The histology shows sweeping fascicles of spindle cells that may exhibit storiform architecture, herringbone patterns, hemangiopericytomatous vessels, and mild nuclear atypia in some cases [23,50] Immunohistochemical features: CD34 immunostaining was positive in the majority of cases, whereas S100 was negative, and pan-TRK immunostaining was positive in many cases [23,50] Genetic features: It may be associated with NTRK3 [23,50] fusion genes Radiological features: N.A. Prognosis: The prognosis varies widely, from low to high malignancy [23,50] Differential diagnosis: Differential diagnoses include MPNST, fibrosarcomatous dermatofibrosarcoma protuberans, solitary fibrous tumor, and synovial sarcoma [23] TRK inhibitor: Sixteen out of 30 patients (53%) with soft tissue sarcoma (STS), including 1 adult-type fibrosarcoma, responded to larotrectinib [49] | |
| Spindle cell sarcomas with hemangiopericytic or myopericytoma-like pattern | Histological features: Histologically, the tumor exhibits a growth pattern similar to hemangiopericytoma or myopericytoma, often with high mitotic activity [22] Immunohistochemical features: Immunohistochemically, some cases of SMA and CD34 positivity were observed [22] Genetic features: It is associated with the NTRK1 fusion gene [22] Radiological features: Typical MRI characteristics include isointensity on T1-weighted images, high signal intensity on T2-weighted images, intense contrast enhancement, and the absence of fatty components or lobular architecture [28] Prognosis: Low-grade sarcomas with myopericytoma or hemangiopericytoma-like morphology often exhibit a more favorable prognosis, though some cases may show aggressive behavior [22,28] Differential diagnosis: Myopericytoma and hemangiopericytoma, solitary fibrous tumor, IFS, myofibromatosis [22] TRK inhibitor: Sixteen out of 30 patients (53%) with soft tissue sarcoma (STS), including two with myopericytoma, responded to larotrectinib [49] | |
| Inflammatory myofibroblastic tumors (IMTs) harboring fusions involving ALK and other kinases | Histological features: Histological features are highly diverse, ranging from inflammatory pseudotumors with few spindle cells and prominent inflammation to highly cellular myofibroblastic proliferations or sarcomatous neoplasms lacking significant inflammation or fibromyxoid stroma [51] Immunohistochemical features: Immunohistochemically, several cases showed positive staining for ALK or ROS1 [51] Genetic features: Cases of IMT with ALK gene rearrangement, ROS1 [51], RET [51] rearrangement, and ETV6-NTRK3 fusion [52,53] have been reported Radiological features: IMTs typically appear as homogeneous or heterogeneous lesions with variable enhancement on contrast-enhanced computed tomography or gadolinium-enhanced MRI, reflecting fibrotic tissue. T1- and T2-weighted MRI sequences often show low signal intensity due to the tumor’s fibrotic composition [54] Prognosis: Three out of four cases reported in two studies have maintained long-term disease-free survival [52,53] Differential Diagnosis: Rhabdomyosarcoma, fibrosarcoma, synovial sarcoma [53,54] TRK inhibitor: Sixteen out of 30 patients (53%) with soft tissue sarcoma (STS), including two with IMT, responded to entrectinib [49] | |
| Spindle cell/sclerosing rhabdomyosarcoma (ssRMS) | Histological features: ssRMS exhibits three histological patterns—fibrosarcoma-like, VGLL2-type, and Triton-like—characterized by fibromatous-like appearance with sparse tumor cells in abundant sclerotic stroma, moderate atypia, and rare mitotic figures [55] Immunohistochemical features: Heterogeneous staining with desmin, myogenin [55] Genetic features: TPM3-NTRK1, SYPL1-BRAF, and TOP2B-RAF1 have been reported [55] Radiological features: The ssRMS show slightly high intensity on T2-weighted and iso- or high intensity on T1-weighted images compared to muscle. On post-contrast images, ssRMS showed hetero- or homogeneous enhancement, as described in a case report [56] Prognosis: Fusion-positive ssRMS has a very good outcome [55] Differential diagnosis: N.A. TRK inhibitor: N.A. | |
| Tumor type . | Clinical features . | |
|---|---|---|
| Infantile fibrosarcoma (IFS) | IFS with canonical ETV6-NTRK3 fusions | Histological features: Interlacing fascicles of spindle cells with focal necrosis, mitoses, and a focal hemangiopericytomatous vascular pattern [33]. Clinically and pathologically, they may mimic vascular/lymphatic malformations [34] Immunohistochemical features: Most cases are positive for vimentin [33] and pan-TRK immunostaining [35] Genetic features: ETV6-NTRK3 [13] Radiological features: CT/MRI shows aberrant vascularization pattern, necrosis, and hemorrhage [27] Prognosis: Generally favorable, better prognosis compared to adult-type fibrosarcoma [36] Differential diagnosis: Vascular/lymphatic malformations [34], infantile myofibromatosis [37] TRK inhibitor: Larotrectinib has shown a 96% response rate (27/28) for IFS [16] |
| IFS-like lesions with related fusion kinases (IFS-like tumors) | Histological features: Monomorphic spindle cells arranged in long, intersecting fascicles [30] Immunohistochemical features: These tumors demonstrated a heterogeneous immunoprofile. While no single marker was consistently expressed across all cases, variable positivity was observed for CD34, S100, smooth muscle actin (SMA), and CD30 [38] Genetic features: A number of fusion genes have been identified, including EML4-NTRK3 [39] and LMNA-NTRK1 [40], BRAF [41], and MET [42] Radiological features: It is possible for tumors to infiltrate adjacent structures [42] Prognosis: These tumors exhibited locally aggressive behavior [38]. Metastases were rare, with lung metastases reported in 1 of 6 cases [38] Differential diagnosis: N.A. TRK inhibitor: One patient showed partial response to lartrectinib with a 93% reduction [43], all three patients with IFS with NTRK1 fusions responded to larotrectinib [16]. One IFS (case 15) with a SPECC1L-NTRK3 fusion was treated with larotrectinib and achieved complete tumor regression [44] | |
| Neurotrophic receptor tyrosine kinase (NTRK)-rearranged spindle cell neoplasm | Lipofibromatosis-like neural tumor (LPF-NT) | Histological features: Spindle-shaped cell tumors with a notably infiltrative growth pattern have been observed in the superficial soft tissues of children and young adults [24,45] Immunohistochemical features: Co-express S100 and CD34 [24,45] Genetic features: The NTRK1 fusion gene is associated [24,45] Radiological features: LPF-LT lesions are frequently characterized as relatively well-defined masses primarily involving subcutaneous tissues, with some cases exhibiting diffuse thickening and minimal extension into deeper soft tissues [46–48] In one reported case, magnetic resonance imaging (MRI) findings included areas of T2 hyperintensity, intermediate T1 signal intensity, and occasional small fat components [46] Prognosis: LPF-LT is predominantly a benign or locally aggressive neoplasm with rarely metastases or disease-related mortality reported in typical cases [24] Differential diagnosis: Lipofibromatosis and low-grade MPNSTs [30] TRK inhibitor: One patient with LPF-NT who had difficulty in primary surgical resection took preoperative entrectinib, and 45% reduction of tumor lead to tumor resection [48] |
| Spindle cell tumors with S100 and CD34 co-reactivity resembling malignant peripheral nerve sheath tumor (MPNST) | Histological features: They resemble MPNSTs but with keloid-like collagen around connective tissue and vessels [25,30]. These tumors show low cellularity, a low mitotic count, and lacked necrosis, although some cases demonstrate a malignant phenotype [25] Immunohistochemical features: Often co-expresses S100 and CD34 [25] Genetic features: Often with NTRK1/2, RAF1 or BRAF fusion genes [25] Radiological features: N.A. Prognosis: Hypocellular tumors are classified as low grade, exhibit a favorable prognosis, and show slow cell growth [25]. However, if the tumor shows increased cell density and mitotic activity, there is an increased likelihood of distant metastasis [25] Differential diagnosis: Low-grade or intermediate-grade MPNSTs [25] TRK inhibitor: Sixteen out of 30 patients (53%) with soft tissue sarcoma (STS), including 6 MPNST, responded to larotrectinib [49] | |
| Adult-type fibrosarcoma | Histological features: The histology shows sweeping fascicles of spindle cells that may exhibit storiform architecture, herringbone patterns, hemangiopericytomatous vessels, and mild nuclear atypia in some cases [23,50] Immunohistochemical features: CD34 immunostaining was positive in the majority of cases, whereas S100 was negative, and pan-TRK immunostaining was positive in many cases [23,50] Genetic features: It may be associated with NTRK3 [23,50] fusion genes Radiological features: N.A. Prognosis: The prognosis varies widely, from low to high malignancy [23,50] Differential diagnosis: Differential diagnoses include MPNST, fibrosarcomatous dermatofibrosarcoma protuberans, solitary fibrous tumor, and synovial sarcoma [23] TRK inhibitor: Sixteen out of 30 patients (53%) with soft tissue sarcoma (STS), including 1 adult-type fibrosarcoma, responded to larotrectinib [49] | |
| Spindle cell sarcomas with hemangiopericytic or myopericytoma-like pattern | Histological features: Histologically, the tumor exhibits a growth pattern similar to hemangiopericytoma or myopericytoma, often with high mitotic activity [22] Immunohistochemical features: Immunohistochemically, some cases of SMA and CD34 positivity were observed [22] Genetic features: It is associated with the NTRK1 fusion gene [22] Radiological features: Typical MRI characteristics include isointensity on T1-weighted images, high signal intensity on T2-weighted images, intense contrast enhancement, and the absence of fatty components or lobular architecture [28] Prognosis: Low-grade sarcomas with myopericytoma or hemangiopericytoma-like morphology often exhibit a more favorable prognosis, though some cases may show aggressive behavior [22,28] Differential diagnosis: Myopericytoma and hemangiopericytoma, solitary fibrous tumor, IFS, myofibromatosis [22] TRK inhibitor: Sixteen out of 30 patients (53%) with soft tissue sarcoma (STS), including two with myopericytoma, responded to larotrectinib [49] | |
| Inflammatory myofibroblastic tumors (IMTs) harboring fusions involving ALK and other kinases | Histological features: Histological features are highly diverse, ranging from inflammatory pseudotumors with few spindle cells and prominent inflammation to highly cellular myofibroblastic proliferations or sarcomatous neoplasms lacking significant inflammation or fibromyxoid stroma [51] Immunohistochemical features: Immunohistochemically, several cases showed positive staining for ALK or ROS1 [51] Genetic features: Cases of IMT with ALK gene rearrangement, ROS1 [51], RET [51] rearrangement, and ETV6-NTRK3 fusion [52,53] have been reported Radiological features: IMTs typically appear as homogeneous or heterogeneous lesions with variable enhancement on contrast-enhanced computed tomography or gadolinium-enhanced MRI, reflecting fibrotic tissue. T1- and T2-weighted MRI sequences often show low signal intensity due to the tumor’s fibrotic composition [54] Prognosis: Three out of four cases reported in two studies have maintained long-term disease-free survival [52,53] Differential Diagnosis: Rhabdomyosarcoma, fibrosarcoma, synovial sarcoma [53,54] TRK inhibitor: Sixteen out of 30 patients (53%) with soft tissue sarcoma (STS), including two with IMT, responded to entrectinib [49] | |
| Spindle cell/sclerosing rhabdomyosarcoma (ssRMS) | Histological features: ssRMS exhibits three histological patterns—fibrosarcoma-like, VGLL2-type, and Triton-like—characterized by fibromatous-like appearance with sparse tumor cells in abundant sclerotic stroma, moderate atypia, and rare mitotic figures [55] Immunohistochemical features: Heterogeneous staining with desmin, myogenin [55] Genetic features: TPM3-NTRK1, SYPL1-BRAF, and TOP2B-RAF1 have been reported [55] Radiological features: The ssRMS show slightly high intensity on T2-weighted and iso- or high intensity on T1-weighted images compared to muscle. On post-contrast images, ssRMS showed hetero- or homogeneous enhancement, as described in a case report [56] Prognosis: Fusion-positive ssRMS has a very good outcome [55] Differential diagnosis: N.A. TRK inhibitor: N.A. | |
Abbreviation: N.A., not available.
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