Abstract
Undifferentiated high-grade pleomorphic sarcoma (UHPS) is a rare soft tissue sarcoma (STS) originated from mesenchyme. UHPS is mostly advanced, aggressive and has poor prognosis. Patients with UHPS tend to have a lower 5-year survival rate than patients with other types of STS. NTRK fusions are commonly found in rare histological tumor types. Among sarcomas, 90% of infantile fibrosarcomas have NTRK fusions. Many other types of sarcomas have also been studied for NTRK fusions. Targeted therapy with NTRK inhibitors, such as Larotrectinib and Entrectinib, leads to response in most patients with NTRK1/2/3 gene fusion-positive tumors. Herein, we present a 68-years old man with UHPS by pathological diagnosis. Next-generation sequencing (NGS) revealed a novel TMTC2-NTRK3 fusion, which was also detected by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). This report broadens the spectrum of NTRK fusions in UHPS and highlights a new target for treatment.
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Abbreviations
- UHPS:
-
Undifferentiated high-grade pleomorphic sarcoma
- PET/CT:
-
Positron emission tomography-computed tomography
- VMAT:
-
Volumetric-modulated arc therapy
- HE:
-
Hematoxylin and eosin
- FISH:
-
Fluorescence in situ hybridization
- IHC:
-
Immunohistochemistry
- SMA:
-
Smooth muscle actin
- NTRK:
-
Neurotrophic tyrosine receptor kinase
- STS:
-
Soft tissue sarcoma
References
Amatu A, Sartore-Bianchi A, Siena S (2016) NTRK gene fusions as novel targets of cancer therapy across multiple tumor types. ESMO Open 1(2):e000023. https://doi.org/10.1136/esmoopen-2015-000023
Caldwell KJ, De La Cuesta E, Morin C, Pappo A, Helmig S (2020) A newborn with a large NTRK fusion positive infantile fibrosarcoma successfully treated with larotrectinib. Pediatr Blood Cancer 67(9):e28330. https://doi.org/10.1002/pbc.28330
Carter-Febres M, Schneller N, Fair D, Solomon D, Perry A, Roy A, Linscott L, Alashari M, Kestle JR, Bruggers CS (2021) Adjuvant maintenance larotrectinib therapy in 2 children with NTRK fusion-positive high-grade cancers. J Pediatr Hematol Oncol 43(7):e987–e990. https://doi.org/10.1097/MPH.0000000000001983
Doebele RC, Drilon A, Paz-Ares L, Siena S, Shaw AT, Farago AF, Blakely CM, Seto T, Cho BC, Tosi D, Besse B, Chawla SP, Bazhenova L, Krauss JC, Chae YK, Barve M, Garrido-Laguna I, Liu SV, Conkling P, John T, Fakih M, Sigal D, Loong HH, Buchschacher GL Jr, Garrido P, Nieva J, Steuer C, Overbeck TR, Bowles DW, Fox E, Riehl T, Chow-Maneval E, Simmons B, Cui N, Johnson A, Eng S, Wilson TR, Demetri GD, Trial investigators (2020) Entrectinib in patients with advanced or metastatic NTRK fusion-positive solid tumors: integrated analysis of three phase 1–2 trials. Lancet Oncol 21(2):271–282. https://doi.org/10.1016/S1470-2045(19)30691-6
Drilon A, Nagasubramanian R, Blake JF, Ku N, Tuch BB, Ebata K, Smith S, Lauriault V, Kolakowski GR, Brandhuber BJ, Larsen PD, Bouhana KS, Winski SL, Hamor R, Wu WI, Parker A, Morales TH, Sullivan FX, DeWolf WE, Wollenberg LA, Gordon PR, Douglas-Lindsay DN, Scaltriti M, Benayed R, Raj S, Hanusch B, Schram AM, Jonsson P, Berger MF, Hechtman JF, Taylor BS, Andrews S, Rothenberg SM, Hyman DM (2017) A next-generation TRK kinase inhibitor overcomes acquired resistance to prior TRK kinase inhibition in patients with TRK fusion-positive solid tumors. Cancer Discov 7(9):963–972. https://doi.org/10.1158/2159-8290.CD-17-0507
Drilon A, Laetsch TW, Kummar S, DuBois SG, Lassen UN, Demetri GD, Nathenson M, Doebele RC, Farago AF, Pappo AS, Turpin B, Dowlati A, Brose MS, Mascarenhas L, Federman N, Berlin J, El-Deiry WS, Baik C, Deeken J, Boni V, Nagasubramanian R, Taylor M, Rudzinski ER, Meric-Bernstam F, Sohal DPS, Ma PC, Raez LE, Hechtman JF, Benayed R, Ladanyi M, Tuch BB, Ebata K, Cruickshank S, Ku NC, Cox MC, Hawkins DS, Hong DS, Hyman DM (2018) Efficacy of larotrectinib in TRK fusion-positive cancers in adults and children. N Engl J Med 378(8):731–739. https://doi.org/10.1056/NEJMoa1714448
Efe T, Heyse TJ, Schofer MD, Fuchs-Winkelmann S, Rexin P, Schmitt J (2010) Malignant fibrous histiocytoma of the distal femur after an arthroscopic anterior cruciate ligament reconstruction: a case report and a review of the literature. BMC Cancer 10:264. https://doi.org/10.1186/1471-2407-10-264
Enjoji M, Hashimoto H, Tsuneyoshi M, Iwasaki H (1980) Malignant fibrous histiocytoma. A clinicopathologic study of 130 cases. Acta Pathol Jpn 30(5):727–41
Hashimoto H (1979) Malignant fibrous histiocytoma: a clinicopathologic study of 130 cases (author’s transl). Fukuoka Igaku Zasshi 70(10):585–613
Kearney MM, Soule EH, Ivins JC (1980) Malignant fibrous histiocytoma: a retrospective study of 167 cases. Cancer 45(1):167–178. https://doi.org/10.1002/1097-0142(19800101)45:1%3c167::aid-cncr2820450127%3e3.0.co;2-8
Knezevich SR, McFadden DE, Tao W, Lim JF, Sorensen PH (1998) A novel ETV6-NTRK3 gene fusion in congenital fibrosarcoma. Nat Genet 18(2):184–187. https://doi.org/10.1038/ng0298-184
Moradi A, Afsharfard A, Atqiaee K (2016) Undifferentiated pleomorphic sarcoma presenting as abdominal pain with a pulsatile mass. Case Rep Surg 2016:8251043. https://doi.org/10.1155/2016/8251043
Nagasubramanian R, Wei J, Gordon P, Rastatter JC, Cox MC, Pappo A (2016) Infantile fibrosarcoma with NTRK3-ETV6 fusion successfully treated with the tropomyosin-related kinase inhibitor LOXO-101. Pediatr Blood Cancer 63(8):1468–1470. https://doi.org/10.1002/pbc.26026
Nakagawara A (2001) Trk receptor tyrosine kinases: a bridge between cancer and neural development. Cancer Lett 169(2):107–114. https://doi.org/10.1016/s0304-3835(01)00530-4
Peiper M, Zurakowski D, Knoefel WT, Izbicki JR (2004) Malignant fibrous histiocytoma of the extremities and trunk: an institutional review. Surgery 135(1):59–66. https://doi.org/10.1016/s0039-6060(03)00325-8
Scott LJ (2019) Larotrectinib: first global approval. Drugs 79(2):201–206. https://doi.org/10.1007/s40265-018-1044-x
Siozopoulou V, Smits E, De Winne K, Marcq E, Pauwels P (2021) NTRK fusions in sarcomas: diagnostic challenges and clinical aspects. Diagnostics (Basel) 11(3):478. https://doi.org/10.3390/diagnostics11030478
Solomon JP, Linkov I, Rosado A, Mullaney K, Rosen EY, Frosina D, Jungbluth AA, Zehir A, Benayed R, Drilon A, Hyman DM, Ladanyi M, Sireci AN, Hechtman JF (2020) NTRK fusion detection across multiple assays and 33,997 cases: diagnostic implications and pitfalls. Mod Pathol 33(1):38–46. https://doi.org/10.1038/s41379-019-0324-7
Weiss SW, Enzinger FM (1978) Malignant fibrous histiocytoma: an analysis of 200 cases. Cancer 41(6):2250–2266. https://doi.org/10.1002/1097-0142(197806)41:6%3c2250::aid-cncr2820410626%3e3.0.co;2-w
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We thank all our colleagues for the intensive studies of this case.
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CB and LZ conceived the idea, and is the patient’s primary oncologist; Drafted the initial draft alongside comprehensive literature review by XY, YJ, and TS; Additional details provided by YW, assisted with material and data collection; ZF revised the draft before an additional round of revisions by all authors.
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Bai, C., Zhang, L., Wang, Y. et al. A novel TMTC2-NTRK3 fusion in undifferentiated high-grade pleomorphic sarcoma. J Cancer Res Clin Oncol 148, 2933–2937 (2022). https://doi.org/10.1007/s00432-022-04249-x
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DOI: https://doi.org/10.1007/s00432-022-04249-x