NTRK-Rearranged Uterine Sarcomas: Clinicopathologic Features of 15 Cases, Literature Review, and Risk Stratification

Abstract

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.

Kinase fusion positive intra‐osseous spindle cell tumors: A series of eight cases with review of the literature

“…In contrast, in a meta‐analysis of 46 NTRK ‐rearranged uterine sarcomas, several adverse prognostic features were established, including a mitotic index ≥8 per 10 HPF, lymphovascular invasion, necrosis, and NTRK3 fusion. Patients with uterine tumors lacking any of these four features had an excellent prognosis 30 . Although patients with BTKF may be eligible for tyrosine kinase inhibitor therapy, 31 none of the patients in this series received such treatment, as most of these older diagnoses preceded the availability of tyrosine kinase inhibitors in clinical use.…”

“…Patients with uterine tumors lacking any of these four features had an excellent prognosis. 30 Although patients with BTKF may be eligible for tyrosine kinase inhibitor therapy, 31 none of the patients in this series received such treatment, as most of these older diagnoses preceded the availability of tyrosine kinase inhibitors in clinical use.…”

Uterine Sarcoma With EML4::NTRK3 Fusion: A Spectrum of Mesenchymal Neoplasms Harboring Actionable Gene Fusions

“…This tumor resembles fibrosarcoma and is composed predominantly of spindle cells with varying degrees of cytologic atypia, arranged in fascicles, with a variable mitotic index and sporadic presence of necrosis. By immunohistochemistry, these cases are usually positive for CD34 and S100, negative for desmin and hormone receptors and positive for pan-Trk antibody 6 . They are commonly located in the uterine cervix, arise in the premenopausal setting, and have an uncertain prognosis.…”

“…Moreover, uncertainty may arise as to the identification of different and rare fusion partners. Although many partners have been described with NTRK family genes, this list continues to expand 6 . In this regard, we report a case of uterine sarcoma with a rare EML4::NTRK3 fusion, described in 3 other uterine cases 6–8 and also recognized in pediatric soft tissue tumors 9 .…”

Uterine sarcomas: clinical practice guidelines for diagnosis, treatment, and follow-up, by Spanish group for research on sarcomas (GEIS)

“… 93 , 94 They exhibit features fibrosarcoma and although few cases have been published to date, they might benefit from targeted therapy. 95 …”