VIM::KMT2A rearranged sarcoma: a rare emerging entity

Sir: In a recent article by Almohsen et al.,1 the authors described the clinicopathological and molecular findings of VIM::KMT2A rearranged sarcomas on two of their cases. This rare but emerging entity was first reported by Yoshida et al.,2 who described it in the femur of a young 30-year-old female patient. Shortly after, Massoth et al.3 reported two additional cases of VIM::KMT2A rearranged sarcomas. All five cases involved adults in their fourth and fifth decade of life, arose in deep soft tissue and demonstrated overlapping morphological features with hypercellular monomorphic proliferation of spindled to ovoid cells with fine vesicular chromatin and high N:C ratio arranged in storiform and fascicular patterns within variable collagenous stroma. Mitotic activity and necrosis varied in all cases. Additionally, all cases showed a similar immunophenotype and were positive for S100 (focal to diffuse), CD99 and Bcl2. RNA sequencing analysis revealed a VIM::KMT2A gene fusion involving exon 4 of VIM and exon 2 of KMT2A in all cases. We recently encountered a similar case arising in a 22-year-old female who initially presented with left upper extremity, neck and back pain together with fatigue and weight loss of 30 pounds. Magnetic resonance imaging (MRI) of the cervical spine demonstrated a large mass involving the paraspinal region (Figure 1A). Computerised tomography (CT)-guided fine needle aspiration of the mass was performed and showed a spindle/round cell neoplasm compatible with sarcoma. Subsequently, the patient was started on chemotherapy, but due to complications with the chemotherapy course and worsening upper extremity weakness and neck pain, the clinical team proceeded with cytoreduction/tumour debulking surgery. Histological evaluation of the resected tumour showed morphological findings congruent with the prior aforementioned studies, including sheet-like to fascicular proliferation of spindled to ovoid or round cells with a high N:C ratio and hyperchromatic nuclei, focal dystrophic calcifications and mitotic figures reaching up to five to 10 high-power fields with no evidence of necrosis (Figure 1B,C). Immunohistochemical stains were positive for S100 (focal, Figure 1D), CD99 (Figure 1E), SSTR2, TLE1, synaptophysin, BCOR and EMA (patchy, Figure 1F) in the lesional cells. Based on the tumour immunophenotype, the differential diagnosis included a malignant round cell sarcoma, not otherwise specified, malignant peripheral nerve sheath tumour and fusion or ITD-related round cell sarcomas, including sarcomas with BCOR-related genetic alterations, CIC-rearranged sarcoma, synovial sarcoma and NTRK-rearranged sarcoma among others. Whole-transcriptome sequencing (RNA-seq) analysis using the TruSeq RNA exome kit with sequencing performed on the NextSeq platform (Illumina, San Diego, CA, USA) identified a VIM::KMT2A fusion (Figure 2) involving exon 4 of VIM and exon 2 of KMT2A, similar to prior studies. Additional targeted next generation sequencing using the Oncomine Comprehensive Assay kit with sequencing performed on the S5 platform (Thermo Fisher, Waltham, MA, USA) identified CTNNB1 (p.G34E, c.101G > A; allele frequency 41%) and ARID1A (p.Y447*, c.1341_1342delinsAT; allele frequency 9%) mutations. This is in accordance with the findings of Massoth et al.,3 who reported concurrent CTNNB1, SMARCB1 and ARID1A mutations in both of their VIM::KMT2A rearranged sarcoma cases. Methylation profiling using the DKFZ sarcoma classifier (version 12.2) was also performed on our case and did not confidently match to any known methylation classes. The patient subsequently received radiation therapy and is currently back on chemotherapy. Although the reported male-to-female ratio for this tumour by Almohsen et al.1 was 4:1, with the majority of patients being in their fourth and fifth decade, our case involved a young female adult in her early third decade of life. Our case represents the first case arising in a young patient in her 20s, the second case to involve a female adult and the sixth case, to our knowledge, of VIM::KMT2A rearranged sarcoma to be reported in the literature. In conclusion, our case adds to the growing pool of VIM::KMT2A rearranged sarcomas. This rare but emerging entity shares uniform histological and immunophenotypical features, including sheet-like to fascicular proliferation of monomorphic spindled to ovoid or round cells with a high N:C ratio and hyperchromatic nuclei, occasional dystrophic calcifications, variable mitosis and necrosis and consistent immunoexpression of S100 and CD99. Our report further confirms and expands the clinicopathological characteristics and molecular features of such rare tumours. The authors declare no conflicts of interest. The data that support the findings of this study are available from the corresponding author upon reasonable request.