The novel finding of an FGFR1::TACC1 fusion in an undifferentiated spindle cell sarcoma of soft tissue with aggressive clinical course

Abstract

We report an aggressive soft tissue sarcoma with FGFR1-TACC1 fusion occurring in the thigh of an 83-year-old man. Microscopically, the tumor was composed of monomorphic spindle cells arranged in intersecting fascicles. The tumor cells showed ovoid nuclei, fine chromatin, indistinct nucleoli, and elongated eosinophilic cytoplasm. Focal increase in nuclear atypia was noted. Immunohistochemistry showed only focal rare positivity to S100, but negative to SOX10, CD34, STAT6, TLE-1, SMA, and other myogenic markers. An extensive panel of immunostains did not reveal a definite lineage of cellular differentiation. The fusion junction of the chimeric transcript involved FGFR1 exon 16 and TACC1 exon 7, which was similar to those reported in other types of neoplasms such as glioblastomas and epithelial cancers. The transcript was predicted to be in-frame and confirmed by Sanger sequencing after reverse transcriptase-polymerase chain reaction. The patient was treated by marginal excision of tumor without receiving adjuvant therapy. He experienced rapid tumor recurrence with distant metastases and succumbed at 3.5 months after presentation. The finding of FGFR1-TACC1 fusion in a high-grade, undifferentiated spindle cell sarcoma of soft tissue is novel and may offer a potential therapeutic target in the near future.

FGFR1 fusions as a novel molecular driver in rhabdomyosarcoma

“…Moreover, clinical activity of an FGFR inhibitor has been reported in a pLGG patient with this fusion 37 . FGFR1::TACC1 fusions were also described in other sarcoma types as isolated case reports, such as a pediatric uterine leiomyosarcoma, 38 uterine sarcoma, 39 and undifferentiated sarcoma 40 . Other variant FGFR1 fusions with alternative gene partners have been also described in benign lesions, such as a calcified chondroid mesenchymal neoplasm with FGFR1::PLAG1 , 41 pediatrc mesenchymal tumors 42 and aneurysmal bone cyst 43 .…”

“…fusions were also described in other sarcoma types as isolated case reports, such as a pediatric uterine leiomyosarcoma, 38 uterine sarcoma, 39 and undifferentiated sarcoma. 40 Other variant FGFR1 fusions with alternative gene partners have been also described in benign lesions, such as a calcified chondroid mesenchymal neoplasm with FGFR1::PLAG1, 41 pediatrc mesenchymal tumors 42 and aneurysmal bone cyst. 43 In contrast, a handful of FGFR fusions have been described in gastrointestinal stromal tumors (GIST) lacking activating KIT/PDGFRA mutations [44][45][46] and in one KIT exon 11 mutant GIST which acquired an FGFR2::TACC2 fusion in the setting of multi-drug resistance.…”

FGFR1 gene fusions in a subset of pediatric mesenchymal tumors: Expanding the genetic spectrum of tumors sharing histologic overlap with infantile fibrosarcoma and “NTRK‐rearranged” spindle cell neoplasms

“…Although rare compared to carcinomas and glial tumors, FGFR alterations have been documented in soft tissue tumors arising in adult patients. FGFR1::TACC1 gene fusions, first discovered in glioblastoma multiforme (GBM), have further been reported in “wild‐type” gastrointestinal stromal tumors, 31 two uterine sarcomas demonstrating co‐expression of CD34 and S100 protein, 32,33 and a high‐grade, undifferentiated spindle cell sarcoma arising in the thigh of an 83‐year‐old man with distant metastasis and aggressive clinical course 34 . Fusions involving FN1 and either FGFR1 or FGFR2 have also been described in multiple cases of soft tissue chondroma, especially those with grungy, chondroblastoma‐like calcification, 35 and several cases of calcified chondroid mesenchymal neoplasm (CCMN) 36 .…”

“…FGFR1::TACC1 gene fusions, first discovered in glioblastoma multiforme (GBM), have further been reported in "wild-type" gastrointestinal stromal tumors, 31 two uterine sarcomas demonstrating co-expression of CD34 and S100 protein, 32,33 and a high-grade, undifferentiated spindle cell sarcoma arising in the thigh of an 83-year-old man with distant metastasis and aggressive clinical course. 34 Fusions involving FN1 and either FGFR1 or FGFR2 have also been described in multiple cases of soft tissue chondroma, especially those with grungy, chondroblastoma-like calcification, 35 and several cases of calcified chondroid mesenchymal neoplasm (CCMN). 36 Unlike the FN1::FGFR1 fusions typically found in phosphaturic mesenchymal tumor, 37 the fusions present in CCMN do not retain any of the Ig domains of FGFR1.…”

Decoding Oncofusions: Unveiling Mechanisms, Clinical Impact, and Prospects for Personalized Cancer Therapies

“…A classic example of transcription factor fusion is the EWSR1::FLI1 fusion, which is a common driver in Ewing sarcoma [79,80]. The most notable protein kinases involved in fusions include the MAST kinases in breast cancer [81], present in 3 to 5% of cases, as well as RET in various cancers (particularly lung and thyroid) [76,[82][83][84] and other RTKs in a variety of tumors [36,36,[85][86][87][88][89][90][91][92][93][94][95][96][97]. Such rearrangements are occasionally cancer-specific, or may be observable in distinctly different cancer types.…”