NTRK-rearranged uterine sarcomas are rare spindle cell neoplasms that typically arise in the uterine cervix of young women. Some tumors recur or metastasize, but features which predict behavior have not been identified to date. Distinguishing these tumors from morphologic mimics is significant because patients with advanced stage disease may be treated with TRK inhibitors. Herein, we present 15 cases of NTRK-rearranged uterine sarcomas, the largest series to date. Median patient age was 35 years (range: 16 to 61). The majority arose in the uterine cervix (n=14) and all but 2 were organ-confined at diagnosis. Tumors were composed of an infiltrative, fascicular proliferation of spindle cells and most showed mild-to-moderate cytologic atypia. All were pan-TRK positive by immunohistochemistry (13/13); S100 (11/13) and CD34 (6/10) were usually positive. RNA or DNA sequencing found NTRK1 (10/13) and NTRK3 (3/13) fusions with partners TPR, TPM3, EML4, TFG, SPECC1L, C16orf72, and IRF2BP2. Unusual morphology was seen in 2 tumors which were originally diagnosed as unclassifiable uterine sarcomas, 1 of which also harbored TP53 mutations. Follow up was available for 9 patients, of whom 3 died of disease. By incorporating outcome data of previously reported tumors, adverse prognostic features were identified, including a mitotic index ≥8 per 10 high-power fields, lymphovascular invasion, necrosis, and NTRK3 fusion. Patients with tumors which lacked any of these 4 features had an excellent prognosis. This study expands the morphologic spectrum of NTRK-rearranged uterine sarcomas and identifies features which can be used for risk stratification.

NTRK重排子宫肉瘤是罕见的梭形细胞肿瘤，通常出现在年轻女性的子宫颈中。有些肿瘤会复发或转移，但迄今为止尚未确定预测行为的特征。将这些肿瘤与形态模拟肿瘤区分开来非常重要，因为晚期疾病患者可能会接受 TRK 抑制剂治疗。在此，我们介绍了 15 例NTRK重排子宫肉瘤病例，这是迄今为止最大的系列。患者中位年龄为 35 岁（范围：16 至 61 岁）。大多数发生在子宫颈（n = 14），除 2 例外，其余所有在诊断时均局限于器官。肿瘤由浸润性、束状增殖的梭形细胞组成，大多数表现出轻度至中度的细胞学异型性。免疫组织化学显示所有患者均为pan-TRK阳性 (13/13)；S100 (11/13) 和 CD34 (6/10) 通常呈阳性。RNA 或 DNA 测序发现NTRK1 (10/13) 和NTRK3 (3/13) 与伴侣TPR、TPM3、EML4、TFG、SPECC1L、C16orf72和IRF2BP2融合。最初诊断为无法分类的子宫肉瘤的 2 个肿瘤出现了异常形态，其中 1 个也含有TP53突变。对 9 名患者进行了随访，其中 3 名患者因病死亡。通过整合先前报告的肿瘤的结果数据，确定了不良预后特征，包括每 10 个高倍视野有丝分裂指数≥8、淋巴血管侵犯、坏死和 NTRK3融合。缺乏这 4 个特征中任何一个的肿瘤患者预后良好。这项研究扩大了NTRK重排子宫肉瘤的形态谱，并确定了可用于风险分层的特征。