Department of Pathology and Genomic Medicine, Thomas Jefferson University Hospital, Philadelphia, PA, USA.
Department of Medical Oncology, Thomas Jefferson University Hospital, Philadelphia, PA, USA.
Diagn Pathol. 2023 Oct 21;18(1):116. doi: 10.1186/s13000-023-01400-1.
Among the three NTRK genes, NTRK2 possesses a tremendous structural complexity and involves tumorigenesis of several types of tumors. To date, only STRN and RBPMS are identified in the fusion with NTRK2 in adult soft tissue tumors. More recently, the highly selective Trk tyrosine kinases inhibitors, including larotrectinib and entrectinib, have shown significant efficacy for treating tumors harboring NTRK fusions and were approved by FDA.
We report a case of sarcoma in a 35-year-old female harboring two STRN-NTRK2 gene fusions, with a good clinical response to first-line larotrectinib treatment. Core biopsy of the 16.5 cm gluteal mass showed a high-grade mesenchymal neoplasm with features reminiscent of a solitary fibrous tumor, but negative for STAT6. In-house next-generation sequencing gene fusion panel showed two in-frame STRN-NTRK2 fusions, which contain the same 5' partner sequence (exon 1-3) of STRN, and the 3' fusion partner starting from either the exon 15 or the exon 16 of NTRK2. Due to the large size and location of the tumor, first-line neoadjuvant therapy with larotrectinib was initiated. The patient has an excellent clinical response with an 83% tumor size reduction by imaging. The tumor was subsequently completely resected. After 130 days, larotrectinib was reinitiated for lung metastasis (up to 7 cm), and a complete resolution was achieved. When compared with NTRK1 and NTRK3, NTRK2 fusions are the least common. Of note, the only other report in the literature on NRTK2 fusion-positive sarcoma also showed solitary fibrous tumor (SFT)-like morphology, and the patient responded well to larotrectinib as the second line adjuvant therapy.
In conclusion, the identification of NTRK2 fusions in patients with soft tissue tumors could significantly improve the clinical outcome through selective NTRK inhibitor therapy, especially in the first-line setting. Prompt RNA-based NGS testing at initial diagnosis may benefit these patients. Our case is among the first few in the literature on NTRK2 fusion sarcoma with first-line larotrectinib therapy in the primary and metastatic setting, with good clinical response and minimal side effects.
在三个 NTRK 基因中，NTRK2 具有巨大的结构复杂性，涉及多种类型肿瘤的发生。迄今为止，只有 STRN 和 RBPMS 被鉴定为成人软组织肿瘤中与 NTRK2 的融合。最近，高度选择性的 Trk 酪氨酸激酶抑制剂，包括拉罗替尼和恩曲替尼，已显示出对携带 NTRK 融合的肿瘤的显著疗效，并被 FDA 批准。
我们报告了一例 35 岁女性的肉瘤病例，该患者携带两个 STRN-NTRK2 基因融合，对一线拉罗替尼治疗有良好的临床反应。16.5cm 臀部长肿块的核心活检显示为高级别间叶性肿瘤，具有孤立性纤维肿瘤的特征，但 STAT6 为阴性。内部下一代测序基因融合面板显示两个 STRN-NTRK2 融合，其包含 STRN 的相同 5' 伴侣序列（外显子 1-3），而 3' 融合伴侣从 NTRK2 的外显子 15 或外显子 16 开始。由于肿瘤的大小和位置较大，首先开始一线新辅助治疗用拉罗替尼。影像学显示肿瘤大小缩小 83%，患者有极好的临床反应。随后完全切除肿瘤。130 天后，因肺转移（最大 7cm）重新开始使用拉罗替尼治疗，完全缓解。与 NTRK1 和 NTRK3 相比，NTRK2 融合是最不常见的。值得注意的是，文献中唯一另一份关于 NRTK2 融合阳性肉瘤的报告也显示出孤立性纤维肿瘤（SFT）样形态，患者对二线辅助治疗的拉罗替尼反应良好。
总之，在软组织肿瘤患者中鉴定出 NTRK2 融合可通过选择性 NTRK 抑制剂治疗显著改善临床结局，特别是在一线治疗中。在初始诊断时进行基于 RNA 的快速 NGS 检测可能对这些患者有益。我们的病例是文献中少数几个关于 NTRK2 融合肉瘤的病例之一，在原发性和转移性疾病中一线使用拉罗替尼治疗，具有良好的临床反应和最小的副作用。
