NTRK Fusions Define a Novel Uterine Sarcoma Subtype With Features of Fibrosarcoma. (June 2018)

• Record Type: Journal Article
• Authors: Chiang, Sarah; Cotzia, Paolo; Hyman, David M.; Drilon, Alexander; Tap, William D.; Zhang, Lei; Hechtman, Jaclyn F.; Frosina, Denise; Jungbluth, Achim A.; Murali, Rajmohan; Park, Kay J.; Soslow, Robert A.; Oliva, Esther; Iafrate, A. John; Benayed, Ryma; Ladanyi, Marc; Antonescu, Cristina R.
• Is Part Of: American journal of surgical pathology. Volume 42:Number 6(2018)
• Publication Date: 2018-06
• Subjects: NTRK -- uterine sarcoma -- fibrosarcoma; Pathology, Surgical -- Periodicals; 617.0705
• DOI: 10.1097/PAS.0000000000001055
• Languages: English
• ISSNs: 0147-5185

Abstract

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. Abstract : Supplemental Digital Content is available in the text.