Undifferentiated pleomorphic sarcoma (UPS) was first described in 1961 by Kauffman as a histiocytic tumor with storiform growth in children [8]. UPS occurs most frequently in patients between 50 and 70 years [9], accounting for 28% of all soft-tissue sarcomas [10]. The major locations of UPS are the lower (49%), upper extremities (19%), while tumors of the abdominal cavity and retroperitoneum account for 16%, and those of the trunk accounts for 9% [11]. UPS includes four histological types: storiform-pleomorphic, giant cell, myxoid, and inflammatory subtypes. The UPS histological morphology varies; however, the classic form comprises spindle-shaped and round histiocytes arranged in a storiform pattern. A majority of UPS patients do not have typical clinical manifestations; so they present to the hospital late because of the relative absence of early clinical symptoms. If symptomatic, patients often suffer from abdominal discomfort, altered bowel motions, hard nodules, and occasionally weight loss, and so on. The tumor is often large at presentation since it usually does not pay attention for a long time.
The primary treatment of UPS is en-bloc resection of the tumor with free margins. However, the prognosis of UPS is extremely poor. Molecular studies suggest that biomarkers such as p-STAT3, SOCS3, MET, and KIT may be prognostic factors for UPS, correlated with different prognoses [12, 13]. There are no effective chemotherapy options at present. The addition of RT to wide surgical excision for UPS has improved local control rates compared with surgery alone [14].
Recently clinical trial data and the subsequent accelerated FDA approval of the selective NTRK inhibitor, Larotrectinib, for treating adult and pediatric patients with solid tumors with NTRK fusion [15, 16]. Larotrectinib has shown a dramatic and durable activity against locally advanced and metastatic solid tumors with NTRK fusions [17]. It is worth noting that this remarkable activity was seen regardless of tumor site of origin, histologic classification, or NTRK fusion type. Previous studies suggested that some cancer types, such as thyroid carcinoma, salivary gland carcinoma, infantile fibrosarcoma, are highly enriched for NTRK fusions [18, 19]. NTRK fusions can be detected in ༜5% non-GIST soft-tissue sarcomas. A retrospective analysis of 38,095 samples from 33,997 patients identified 87 patients with oncogenic NTRK1-3 fusions. NTRK fusions are seen in 0.68% of sarcoma and are seen in 17.7% of inflammatory myofibroblastic tumors [20]. Although most NTRK-fusion sarcomas occur in pediatric populations, they also affect a smaller number of adults. Thus far, some researchers have studied the incidence of NTRK3 fusion proteins in sarcoma; all of them are ETV6-NTRK3. In Ramamoorthy Nagasubramanian’s paper which first reported an infantile fibrosarcoma patient with ETV6-NTRK3 fusion successfully treated with the tropomyosin-related kinase inhibitor LOXO-101 [21]. In the second study, Kenneth J. Caldwell reported that a newborn with ETV6-NTRK3 fusion-positive infantile fibrosarcoma was successfully treated with Larotrectinib [22]. While in the third paper [23], the patient was a child with ETV6-NTRK3 fusion-positive undifferentiated embryonal sarcoma of the kidney, successfully treated with adjuvant maintenance Larotrectinib therapy. However, the frequency of NTRK fusions, especially NTRK3 in UPS, and especially in Chinese UPS patients is not clear. So, it is the first time reported another NTRK3 fusion type, and it is a little different in the clinical response of Larotrectinib, which in our patient only got a stable disease (SD) result. Unresponsiveness to an NTRK inhibitor may be due either to the lack of an NTRK fusion or to the development of a resistance mechanism [24], such as acquired mutations in the kinase domain of the NTRK genes [25], including a mutation in NTRK3 that changes amino acid 623 in TRKC from glycine to arginine (G623R) or a similar mutation in the paralogous residue, G595R of NTRK1/TRKA. In the 2020 ASCO case report [26], they had discussed response and mechanisms of resistance to Larotrectinib and Selitrectinib in metastatic undifferentiated sarcoma harboring an oncogenic fusion of NTRK1, and they discovered the NTRK1 solvent-front mutation, which facilitates the tumor initially developed resistance to Larotrectinib. The gain-of-function KRAS G12V mutation was identified as a second mutation that might alter the immune microenvironment and affected TRK-inhibitor's function. However, our patient was detected with NTRK3 fusion and expressed NTRK3 kinase domain protein, and it is still not a good result when treated with Larotrectinib. We will focus on the patient’s gained mutation in the future.
In our case, we identified a novel TMTC2-NTRK3 fusion-positive tumor in a Chinese UPS patient by DNA-Seq, IHC, and FISH, which expanded the NTRK fusion spectrum and reflected our clinical practice.