Kinase fusion positive intra-osseous spindle cell tumors: A series of eight cases with review of the literature

Abstract

Mesenchymal spindle cell tumors with kinase fusions, often presenting in superficial or deep soft tissue locations, may rarely occur in bone. Herein, we describe the clinicopathologic and molecular data of eight bone tumors characterized by various kinase fusions from our files and incorporate the findings with the previously reported seven cases, mainly as single case reports. In the current series all but one of the patients were young children or teenagers, with an age range from newborn to 59 years (mean 19 years). Most tumors (n = 5) presented in the head and neck area (skull base, mastoid, maxilla, and mandible), and remaining three in the tibia, pelvic bone, and chest wall. The fusions included NTRK1 (n = 3), RET (n = 2), NTRK3 (n = 2), and BRAF (n = 1). In the combined series (n = 15), most tumors (73%) occurred in children and young adults (<30 years) and showed a predilection for jaw and skull bones (40%), followed by long and small tubular bones (33%). The fusions spanned a large spectrum of kinase genes, including in descending order NTRK3 (n = 6), NTRK1 (n = 4), RET (n = 2), BRAF (n = 2), and RAF1 (n = 1). All fusions confirmed by targeted RNA sequencing were in-frame and retained the kinase domain within the fusion oncoprotein. Similar to the soft tissue counterparts, most NTRK3-positive bone tumors in this series showed high-grade morphology (5/6), whereas the majority of NTRK1 tumors were low-grade (3/4). Notably, all four tumors presenting in the elderly were high-grade spindle cell sarcomas, with adult fibrosarcoma (FS)-like, malignant peripheral nerve sheath tumor (MPNST)-like and MPNST phenotypes. Overall, 10 tumors had high-grade morphology, ranging from infantile and adult-types FS, MPNST-like, and MPNST, whereas five showed benign/low-grade histology (MPNST-like and myxoma-like). Immunohistochemically (IHC), S100 and CD34 positivity was noted in 57% and 50%, respectively, while co-expression of S100 and CD34 in 43% of cases. One-third of tumors (4 high grade and the myxoma-like) were negative for both S100 and CD34. IHC for Pan-TRK was positive in all eight NTRK-fusion positive tumors tested and negative in two tumors with other kinase fusions. Clinical follow-up was too limited to allow general conclusions.

Keywords: NTRK; RET; bone; fibrosarcoma; fusion; malignant peripheral nerve sheath tumor; sarcoma.

Figure 1.

BTKF (bone tumor with kinase fusion) with low-grade MPNST-like and myxoma-like morphology. A-E, a 2.5 cm LG-MPNST-like lesion with LMNA::NTRK1 fusion (case #4) involving maxilla showing aggressive clinical features with CT imaging including cortical breakthrough and soft tissue extension (A). This tumor is composed of vague fascicles of bland spindle cells infiltrating bone and cartilage (B). At higher power the tumor shows haphazardly arranged uniform spindle cells, dense keloid-like stromal changes and marked perivascular hyalinization (C). The tumor is positive for Pan-TRK (D). E, mandible tumor representing LG-MPNST with LMNA::NTRK1 fusion (case #3) showing fascicles of uniform eosinophilic myofibroblast-like spindle cells. F, Myxoma-like histology: skull base tumor with KIF5B::RET fusion (case #8). This hypocellular and hypovascular tumor is composed of bland stellate cells in an abundant myxoid background and indistinguishable from myxoma of bone.

Figure 2.

Primary MPNST of bone with UPF2::NTRK3 fusion, occurring in the proximal tibia of a-29-year-old female. Plain radiograph shows an ill-defined destructive bone tumor with cortical breakthrough and soft tissue extension (A). The tumor is composed of perpendicular fascicles of monomorphic hyperchromatic (blue) spindle cells (B-C), which show expression of cytokeratin (D) and loss of trimethylated histone protein H3K27 (E).

FIGURE 3.

BTKF showing high-grade FS-like patterns. A-D IFS with ETV6::NTRK3 fusion (case #1) composed of a cystic lesion surrounded by a thick fibrous capsule with mural nodules (A) showing cystic hemorrhagic change (B) and solid growth with HPC-like vascular pattern and heavy lymphocytic infiltrate (C), and IHC staining for Pan-TRK (D)plump epithelioid cells (D). E-F IFS-like tumor with CLIP2::RET fusion (case #2) composed of fascicles of spindle cells in herringbone (E) and intersecting patterns (F).