Confirmatory diagnosis and successive chemotherapeutic treatments of metastatic skeletal <em>EWSR1::NFATC2</em> sarcoma: A case report

Urasaki,Tetsuya; Ono,Makiko; Yamashita,Kyoko; Tanizawa,Taisuke; Togashi,Yuki; Ohmoto,Akihiro; Suto,Hirotaka; Oki,Ryosuke; Wang,Xiaofei; Nakao,Takehiro; Sato,Yasuyoshi; Fukuda,Naoki; Nakano,Kenji; Tomomatsu,Junichi; Saito,Masanori; Hayakawa,Keiko; Takeuchi,Kengo; Matsumoto,Seiichi; Ae,Keisuke; Takahashi,Shunji

doi:10.3892/ol.2024.14854

Confirmatory diagnosis and successive chemotherapeutic treatments of metastatic skeletal EWSR1::NFATC2 sarcoma: A case report

Authors:
- Tetsuya Urasaki
- Makiko Ono
- Kyoko Yamashita
- Taisuke Tanizawa
- Yuki Togashi
- Akihiro Ohmoto
- Hirotaka Suto
- Ryosuke Oki
- Xiaofei Wang
- Takehiro Nakao
- Yasuyoshi Sato
- Naoki Fukuda
- Kenji Nakano
- Junichi Tomomatsu
- Masanori Saito
- Keiko Hayakawa
- Kengo Takeuchi
- Seiichi Matsumoto
- Keisuke Ae
- Shunji Takahashi
View Affiliations

Affiliations: Department of Medical Oncology, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo 135‑8550, Japan, Department of Pathology, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo 135‑8550, Japan, Department of Orthopedics, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo 135‑8550, Japan
Published online on: December 20, 2024 https://doi.org/10.3892/ol.2024.14854
Article Number: 108

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

EWSR1::NFATC2 sarcoma is rare and its clinical features remain unclear. Given the similarity in presentation, it is possible that previously reported cases of Ewing‑like adamantinoma may have been EWSR1::NFATC2 sarcoma. The present case report describes a tumor in a 55‑year‑old man that was originally thought to be a Ewing‑like adamantinoma, but was recently found to be an EWSR1::NFATC2 sarcoma following direct sequencing. The patient experienced pain in their left lower leg at 38 years of age. The initial pathological diagnosis was ‘epithelioid malignant tumor of the left tibia suggesting Ewing‑like adamantinoma’. The patient underwent wide excision of the tumor in their left tibia with left total knee arthroplasty and a medial gastrocnemius muscle flap. Thereafter, the patient continued with no evidence of recurrent or metastatic disease; however, 14 years later, they developed multiple lesions in the left lung, left pleural dissemination, and enlargement of the mediastinal, left hilar and juxtaesophageal lymph nodes. Pathological diagnosis of transbronchial lung biopsy was consistent with ‘Ewing‑like adamantinoma’. The patient received doxorubicin‑based systemic chemotherapy as first‑line therapy, which resulted in stable disease. After disease progression, the patient received eribulin monotherapy, which resulted in stable disease for 15 months. Reverse transcription‑polymerase chain reaction followed by direct sequencing revealed an in‑frame EWSR1::NFATC2 fusion where exon 8 of EWSR1 (ENST00000397938.7) was fused to exon 3 of NFATC2 (ENST00000371564.8), and their diagnosis was changed to EWSR1::NFATC2 sarcoma. The disease progressed, left pleural dissemination progressed, left pleural effusion increased and peritoneal dissemination in the left paracolic gutter was suspected. Therefore, the patient was started on trabectedin monotherapy during 16 months of stable disease, and thereafter received pazopanib after they presented with progressive disease on prior trabectedin monotherapy. It is likely that there are more patients with undiagnosed EWSR1::NFATC2 sarcoma. To make a definitive diagnosis, a thorough investigation should be performed.

View Figures

View References

1	Gaspar N, Hawkins DS, Dirksen U, Lewis IJ, Ferrari S, Le Deley MC, Kovar H, Grimer R, Whelan J, Claude L, et al: Ewing sarcoma: Current management and future approaches through collaboration. J Clin Oncol. 33:3036–3046. 2015. View Article : Google Scholar : PubMed/NCBI
2	The WHO Classification of Tumours Editorial Board, . WHO Classification of Tumours: Soft Tissue and Bone Tumours. 3.5th edition. International Agency for Research on Cancer; Lyon: 2020
3	Szuhai K, Ijszenga M, de Jong D, Karseladze A, Tanke HJ and Hogendoorn PC: The NFATc2 gene is involved in a novel cloned translocation in a Ewing sarcoma variant that couples its function in immunology to oncology. Clin Cancer Res. 15:2259–2268. 2009. View Article : Google Scholar : PubMed/NCBI
4	Yoshida KI, Machado I, Motoi T, Parafioriti A, Lacambra M, Ichikawa H, Kawai A, Antonescu CR and Yoshida A: NKX3-1 is a useful immunohistochemical marker of EWSR1-NFATC2 sarcoma and mesenchymal chondrosarcoma. Am J Surg Pathol. 44:719–728. 2020. View Article : Google Scholar : PubMed/NCBI
5	Charville GW, Wang WL, Ingram DR, Roy A, Thomas D, Patel RM, Hornick JL, van de Rijn M and Lazar AJ: EWSR1 fusion proteins mediate PAX7 expression in ewing sarcoma. Mod Pathol. 30:1312–1320. 2017. View Article : Google Scholar : PubMed/NCBI
6	Toki S, Wakai S, Sekimizu M, Mori T, Ichikawa H, Kawai A and Yoshida A: PAX7 Immunohistochemical evaluation of ewing sarcoma and other small round cell tumours. Histopathology. 73:645–652. 2018. View Article : Google Scholar : PubMed/NCBI
7	Wang GY, Thomas DG, Davis JL, Ng T, Patel RM, Harms PW, Betz BL, Schuetze SM, McHugh JB, Horvai AE, et al: EWSR1-NFATC2 translocation-associated sarcoma clinicopathologic findings in a rare aggressive primary bone or soft tissue tumor. Am J Surg Pathol. 43:1112–1122. 2019. View Article : Google Scholar : PubMed/NCBI
8	Perret R, Escuriol J, Velasco V, Mayeur L, Soubeyran I, Delfour C, Aubert S, Polivka M, Karanian M, Meurgey A, et al: NFATc2-rearranged sarcomas: Clinicopathologic, molecular, and cytogenetic study of 7 cases with evidence of AGGRECAN as a novel diagnostic marker. Mod Pathol. 33:1930–1944. 2020. View Article : Google Scholar : PubMed/NCBI
9	Sadri N, Barroeta J, Pack SD, Abdullaev Z, Chatterjee B, Puthiyaveettil R, Brooks JS, Barr FG and Zhang PJ: Malignant round cell tumor of bone with EWSR1-NFATC2 gene fusion. Virchows Arch. 465:233–239. 2014. View Article : Google Scholar : PubMed/NCBI
10	Lipper S and Kahn LB: Case report 235. Ewing-like adamantinoma of the left radial head and neck. Skeletal Radiol. 10:61–66. 1983. View Article : Google Scholar : PubMed/NCBI
11	Makise N, Yoshida K, Iijima T, Yoshida A, Ushiku T and Ishida T: Skeletal EWSR1-NFATC2 sarcoma previously diagnosed as ewing-like adamantinoma: A case report and literature review emphasizing its unique radiological features. Pathol Int. 71:614–620. 2021. View Article : Google Scholar : PubMed/NCBI
12	Seligson ND, Maradiaga RD, Stets CM, Katzenstein HM, Millis SZ, Rogers A, Hays JL and Chen JL: Multiscale-omic assessment of EWSR1-NFATc2 fusion positive sarcomas identifies the mTOR pathway as a potential therapeutic target. NPJ Prec Oncol. 5:432021. View Article : Google Scholar
13	Watson S, Perrin V, Guillemot D, Reynaud S, Coindre JM, Karanian M, Guinebretière JM, Freneaux P, Le Loarer F, Bouvet M, et al: Transcriptomic definition of molecular subgroups of small round cell sarcomas. J Pathol. 245:29–40. 2018. View Article : Google Scholar : PubMed/NCBI
14	Shaheen M, Wurtz LD, Brocken EG and Warmke LM: EWSR1: NFATC2-rearranged sarcoma in bone-case report and review of the literature. Hum Pathol. 30:3006802022.
15	Diaz-Perez JA, Nielsen GP, Antonescu C, Taylor MS, Lozano-Calderon SA and Rosenberg AE: EWSR1/FUS-NFATc2 rearranged round cell sarcoma: Clinicopathological series of 4 cases and literature review. Hum Pathol. 90:45–53. 2019. View Article : Google Scholar : PubMed/NCBI
16	Bode-Lesniewska B, Fritz C, Exner GU, Wagner U and Fuchs B: EWSR1-NFATC2 and FUS-NFATC2 gene fusion-associated mesenchymal tumors: Clinicopathologic correlation and literature review. Sarcoma. 2019:93863902019. View Article : Google Scholar : PubMed/NCBI
17	Tsuda Y, Zhang L, Meyers P, Tap WD, Healey JH and Antonescu CR: The clinical heterogeneity of round cell sarcomas with EWSR1/FUS gene fusions: Impact of gene fusion type on clinical features and outcome. Genes Chromosomes Cancer. 59:525–534. 2020. View Article : Google Scholar : PubMed/NCBI
18	Gouda MA, Zarzour MA, Vaporciyan AA, Kairemo K, Chuang HH and Subbiah V: Activity of pazopanib in EWSR1-NFATC2 translocation associated bone sarcoma. Oncoscience. 10:44–53. 2023. View Article : Google Scholar : PubMed/NCBI
19	Kosemehmetoglu K, Rekhi B, Erdem ZB, Yildiz AE and Comunoglu N: Clinicopathological features of three rare EWSR1::NFATC2 sarcomas of bone and soft tissues. Int J Surg Pathol. 32:1275–1285. 2024. View Article : Google Scholar : PubMed/NCBI
20	Kawai A, Araki N, Sugiura H, Ueda T, Yonemoto T, Takahashi M, Morioka H, Hiraga H, Hiruma T, Kunisada T, et al: Trabectedin monotherapy after standard chemotherapy versus best supportive care in patients with advanced, translocation-related sarcoma: A randomized, open-label, phase 2 study. Lancet Oncol. 16:406–416. 2015. View Article : Google Scholar : PubMed/NCBI
21	Kawaguchi K, Nakano K, Urasaki T, Fukuda N, Taira S, Ono M, Tomomatsu J, Nishizawa M, Ae K, Matsumoto S and Takahashi S: Retrospective analysis of trabectedin therapy for soft tissue sarcoma. In Vivo. 33:1609–1614. 2019. View Article : Google Scholar : PubMed/NCBI
22	Kobayashi H, Iwata S, Wakamatsu T, Hayakawa K, Yonemoto T, Wasa J, Oka H, Ueda T and Tanaka S: Efficacy and safety of trabectedin for patients with unresectable and relapsed soft-tissue sarcoma in Japan: A Japanese musculoskeletal oncology group study. Cancer. 126:1253–1263. 2020. View Article : Google Scholar : PubMed/NCBI
23	Machado I, Llombart-Bosch A, Charville GW, Navarro S, Domínguez Franjo MP, Bridge JA and Linos K: Sarcomas with EWSR1::Non-ETS fusion (EWSR1::NFATC2 and EWSR1::PATZ1). Surg Pathol Clin. 17:31–35. 2024. View Article : Google Scholar : PubMed/NCBI