Recurrent RET gene fusions in paediatric spindle mesenchymal neoplasms*

Abstract

Aims: The classification of paediatric spindle mesenchymal tumours is evolving, and the spectrum of socalled 'infantile fibrosarcoma' has expanded to include tumours with NTRK, BRAF and MET gene fusions. RETrearranged paediatric spindle cell neoplasms are an emerging group; there is sparse literature on their clinical, pathological and genetic features, and their nosological place in the canon of soft tissue tumours is uncertain. In this study, we report five RET-rearranged paediatric spindle cell tumours with fusion partners MYH10, KIAA1217 and CLIP2. Methods and results: The tumours occurred in the pelvic region, paraspinal region, kidney and subcutaneous tissue of hand and abdomen. The patients' ages ranged from 6 months to 13 years (median 1 year). The tumours were composed of monomorphic spindle cells arranged in a fascicular pattern. Lesional cells had minimally atypical ovoid or tapered nuclei and pale cytoplasm with indistinct borders. Necrosis was not identified. Mitoses numbered three to 12 per 10 high-power field. Cases showed inconsistent and variable expression of S100, CD34 and SMA. Clinical behaviour ranged from small lesions potentially cured by simple resection to large lesions exhibiting metastasis, but responsive to kinase inhibitor therapy. Conclusions: Our findings help to define RET-rearranged spindle cell tumours. Although it is likely that these tumours comprise part of the morphological and clinical spectrum of infantile fibrosarcoma (IFS), identification of RET gene alteration is important for its unique therapeutic implications.

Emerging soft tissue tumors with kinase fusions: An overview of the recent literature with an emphasis on diagnostic criteria

“…There are two series to date reporting recurrent RET fusions in STT 4,23 . Both studies highlight their strong predilection for children, including infants, and their diverse histologic spectrum, closely reproducing the phenotype observed in NTRK ‐fusion positive tumors.…”

RET Gene Fusions in Malignancies of the Thyroid and Other Tissues

“…MYH10-RET fusion, in particular, is, thus far, the most common RET lesion in spindle mesenchymal tumor and it was also identified in a case of infantile myofibromatosis [36,54]. The morphology of RET fusion-positive spindle mesenchymal samples largely overlaps that of NTRK-positive ones [31,36].…”

“…Moreover, translocations t(10;22)(q11;q11) and t(6;10)(q27;q11) generating BCR-RET and FGFR1OP-RET fusions have been identified in single cases of chronic myelomonocytic leukemia (CMML) and primary myelofibrosis (PMF) with secondary acute myeloid leukemia (AML) [26,122]. Finally, pediatric spindle mesenchymal tumors are a heterogeneous group of rare soft tissue neoplasms with fibroblastic or neural-like differentiation, that include infantile fibrosarcoma and others [31,36]. These tumors typically feature rearrangements involving ALK, BRAF, NTRK1, NTRK2, NTRK3, and MET kinases [36].…”

“…Finally, pediatric spindle mesenchymal tumors are a heterogeneous group of rare soft tissue neoplasms with fibroblastic or neural-like differentiation, that include infantile fibrosarcoma and others [31,36]. These tumors typically feature rearrangements involving ALK, BRAF, NTRK1, NTRK2, NTRK3, and MET kinases [36]. A significant fraction of them has been discovered to harbor RET fusions, including the rare MYH10-, CLIP2-, KIAA1217-SPECC1L-, KHDRBS1-, VCL-, and TFG-RET fusions [13,31,36,54,58,71,75,123].…”

“…A significant fraction of them has been discovered to harbor RET fusions, including the rare MYH10-, CLIP2-, KIAA1217-SPECC1L-, KHDRBS1-, VCL-, and TFG-RET fusions [13,31,36,54,58,71,75,123]. MYH10-RET fusion, in particular, is, thus far, the most common RET lesion in spindle mesenchymal tumor and it was also identified in a case of infantile myofibromatosis [36,54]. The morphology of RET fusion-positive spindle mesenchymal samples largely overlaps that of NTRK-positive ones [31,36].…”