NTRK Fusions Define a Novel Uterine Sarcoma Subtype With Features of Fibrosarcoma

Abstract

Tropomyosin receptor kinase (Trk) inhibitors have shown high response rates in patients with tumors harboring NTRK fusions. We identified 4 NTRK fusion-positive uterine sarcomas that should be distinguished from leiomyosarcoma and undifferentiated uterine sarcoma. NTRK rearrangements were detected by fluorescence in situ hybridization (FISH) and/or targeted RNA or DNA sequencing in 4 undifferentiated uterine sarcomas with spindle cell morphology. Because of histologic overlap with leiomyosarcoma, TrkA and pan-Trk immunohistochemistry was performed in 97 uterine leiomyosarcomas. NTRK1 and NTRK3 FISH was performed on tumors with TrkA or pan-Trk staining. We also performed whole transcriptome RNA sequencing of a leiomyosarcoma with TrkA expression and targeted RNA sequencing of 2 additional undifferentiated uterine sarcomas. FISH and/or targeted RNA or DNA sequencing in the study group showed TPM3-NTRK1, LMNA-NTRK1, RBPMS-NTRK3, and TPR-NTRK1 fusions. All tumors were composed of fascicles of spindle cells. Mitotic index was 7 to 30 mitotic figures per 10 high power fields; tumor necrosis was seen in 2 tumors. Desmin, estrogen receptor, and progesterone receptor were negative in all tumors, while pan-Trk was expressed in all tumors with concurrent TrkA staining in 3 of them. TrkA and/or pan-Trk staining was also seen in 6 leiomyosarcomas, but these tumors lacked NTRK fusions or alternative isoforms by FISH or whole transcriptome sequencing. No fusions were detected in 2 undifferentiated uterine sarcomas. NTRK fusion-positive uterine spindle cell sarcomas constitute a novel tumor type with features of fibrosarcoma; patients with these tumors may benefit from Trk inhibition. TrkA and pan-Trk expression in leiomyosarcomas is rare and does not correlate with NTRK rearrangement.

Figure 1.

Morphologic features of four NTRK fusion-positive uterine sarcomas. A) Haphazard fascicles of spindle cells arranged in a storiform pattern and associated with scattered lymphocytes. Herringbone pattern of spindle cells with mild nuclear atypia in one tumor (B) and rare pleomorphic cells in another (C). D) Spindle cells with mild to moderate nuclear atypia forming fascicles (right) adjacent to cells with marked pleomorphism and multinucleation.

Figure 2.

Confirmation of RBPMS-NTRK3 fusion in a uterine sarcoma by targeted RNA sequencing.

Figure 3.

LMNA-NTRK1 gene fusion demonstrated by FISH. A two-color fusion assay was applied showing the NTRK1 (green, telomeric) and LMNA (red, centromeric) signals come together as a yellow fused signal (white arrows).

Figure 4.

Trk expression patterns in uterine sarcomas with NTRK gene rearrangement. A and B) Diffuse cytoplasmic TrkA and pan-Trk expression in tumors with TPM3-NTRK1 and RBPMS-NTRK3 fusions, respectively. C) Weakly cytoplasmic and strongly perinuclear staining in the tumor harboring LMNA-NTRK1 fusion. D) Strong and diffuse pan-Trk expression with mostly cytoplasmic and dot-like aggregates (top inset) as well as rare nuclear staining accentuation of the nuclear envelope (bottom inset) in the tumor harboring TPR-NTRK1 fusion.