Neurofibrosarcoma Revisited

Abstract

Uterine sarcomas with variable CD34 and S100 expression represent an emerging class of tumor in the female genital tract which commonly presents in the endocervix of premenopausal women. Initial molecular characterization identified NTRK1 and NTRK3 gene fusions as oncogenic drivers in these tumors; however, the repertoire of genetic alterations is likely more diverse given the recent discovery of PDGFB and RET gene fusions in similarly described tumors. Importantly, these fusion events lead to the aberrant activation of kinases that are potentially therapeutically targetable; therefore, recognizing this class of tumor becomes critical for initiating the molecular testing required for an accurate diagnosis and identification of clinically actionable fusions. Here, we report our institutional experience with 12 cases of uterine spindle cell sarcomas harboring kinase-related fusions. Patients ranged from 21 to 80 years old (median, 38 y) and presented either asymptomatically or with pelvic pain and/or uterine bleeding. Eleven (92%; 11/12) tumors were localized to the cervix and 1 (8%; 1/12) tumor was localized in the anterior fundus of the uterine corpus. Tumors ranged in size from 1.5 to 15.0 cm (median, 6.0 cm) and were histologically characterized by a moderately cellular, infiltrative proliferation of spindle cells with features of benign gland entrapment, stromal collagen deposition, perivascular hyalinization, occasionally myxoid stroma, a lymphocytic infiltrate, occasional nuclear pseudoinclusions, and a pseudophyllodes architecture. RNA-sequencing identified NTRK1 (8/12), NTRK3 (1/12), and PDGFB (2/12) gene fusions, which have been previously implicated in this tumor class, as well as a novel FGFR1-TACC1 (1/12) fusion. All tumors in this cohort showed coexpression of CD34 and S100 by immunohistochemistry except for those tumors with PDGFB fusions which showed solely CD34 expression. Of the 10 surgically resected tumors with follow-up, outcomes best correlated with the stage of disease. One of 4 patients with stage IA tumors (1/4) had recurrences, half of the stage IB (2/4) tumors had recurrences and all of the stage IIB tumors (2/2) had recurrences and died of disease. Future studies are still required to better understand the spectrum of genetic alterations as well as evaluate the efficacy of targeted kinase inhibitors in this class of tumor.

Uterine Sarcoma With FGFR1-TACC1 Gene Fusion: A Case Report and Review of the Literature

“…Unlike the index case, SMA was focally positive in our case, but both tumors were negative for desmin, h-caldesmon, and ER (3). Interestingly, while pan-Trk immunohistochemistry was not done in our tumor, it showed patchy expression in the index case, highlighting a potential pitfall in using immunohistochemistry to predict an oncogenic NTRK fusion (3).…”

“…Devereaux et al (3) hypothesize that these tumors arise from some form of fibroblast-like progenitor. The unique clinical and morphologic features of these kinase gene fusion-associated sarcomas warrants further study.…”

“…For instance, the predilection of these tumors to be associated with a brisk lymphoplasmacytic infiltrate raises the question of whether they may represent promising targets for adjuvant immunotherapy. Thus, further immuno-oncologic characterization may be a promising area for investigation (3).…”

Fibroblast Growth Factor Receptor (FGFR) Signaling in GIST and Soft Tissue Sarcomas

“…These fusions have not been directly confirmed to be oncogenic in GIST, however, they have been reported in other cancers. In particular, a fusion between the FGFR1 and HOOK3 genes was reported in the case of acute lymphoblastic leukemia [ 21 ], whereas FGFR1-TACC1 fusion is common in primary brain tumors such as extra-ventricular neurocytoma [ 22 ] and glioblastoma [ 23 ], and has been recently reported in a case of uterine spindle cell sarcoma [ 24 ].…”

Oncogenic FGFR Fusions Produce Centrosome and Cilia Defects by Ectopic Signaling

“…The FGFR1 fusion with transforming acidic coiled-coil containing protein 1 (TACC1) was found in various types of tumors arising within the central nervous system (14 of 15; Table 1) [186,187,[204][205][206][207][208][209][210][211]. FGFR1-TACC1 transformed C3H10T1/2 and Rat1A fibrob-lasts [187,263], and the xenografted astrocytes stably expressing FGFR1-TACC1 gave rise to gliomas [187].…”