A novel case of an infantile fibrosarcoma-like tumor with KIAA1549-BRAF translocation and an oncogenic NF2p.Q459* SNV with potential clinical significance

We report a case of a right gluteal mass from the sacroiliac joint to the knee of an infant girl. Biopsy showed histopathological features similar to infantile fibrosarcoma (IFS). However, unlike most IFS, no ETV6-NTRK3 fusion gene abnormality was detected. Molecular analysis with TruSight RNA Pan-Cancer Panel detected the presence of KIAA1549-BRAF translocation and an oncogenic NF2p.Q459* SNV with potential clinical significance. A review revealed that the combination of this patient’s tumor site with the presence of a KIAA1549-BRAF translocation abnormality and an accompanying single nucleotide variant has not been previously described. The detection of this translocation abnormality raises the possibility that the spindle cell tumors in infants with an absence of the ETV6-NTRK3 fusion gene abnormality might have a distinct pathogenetic mechanism different from the previously known IFS and congenital mesoblastic nephroma. Furthermore, the discovery of BRAF translocation and its aberrant signaling of the mitogen-activated protein kinase (MAPK) pathway in this tumor contributes to the promise of clinical benefit of using the MEKi trametinib for the treatment of progressive disease that is refractory to conventional chemotherapy.

Update on Superficial Spindle Cell Mesenchymal Tumors in Children

The diagnosis of cutaneous and subcutaneous spindle cell neoplasms in children is often challenging and has potential therapeutic and prognostic implications. Although correctly diagnosing dermatofibrosarcoma protuberans and infantile fibrosarcoma is paramount, pathologists should not ignore a number of diagnostic pitfalls linked to mostly rare tumors with completely different clinical outcomes. In the last decade, a spectrum of novel entities has been described; information from molecular biology has helped to shape this new landscape for spindle cell tumors. Here, we review the most noteworthy neoplasms in this spectrum, with a focus on their histological similarities: fibroblastic connective tissue nevus, medallion-like dermal dendrocyte hamartoma, or plaque-like CD34-positive dermal fibroma, which share features with fibrous hamartoma of infancy; lipofibromatosis and lipofibromatosis-like neural tumor; and plexiform myofibroblastoma, a recently described neoplasm that should be distinguished from plexiform fibrohistiocytic tumor. These tumors also have genetic similarities, particularly gene rearrangements involving NTRK3 or NTRK1. These genetic features are not only essential for the differential diagnosis of infantile fibrosarcoma but are also of diagnostic value for lipofibromatosis-like neural tumors. The more recently described RET, RAF1, and BRAF gene fusions are also discussed.

Targeted Therapy Using the Selective Tropomyosin Kinase Receptor Inhibitor Larotrectinib in an Infant with Infantile Fibrosarcoma with a TPM3–NTRK1 Gene Fusion with Lung and Central Nervous System Metastases: Case Report

This case report describes the outcomes of tropomyosin receptor kinase (TRK) inhibitor treatment in an infant with an infantile fibrosarcoma (IFS) with a TPM3–NTRK1 gene fusion. The IFS on the left foot was refractory to chemotherapy and was partially resected. After 5 months, there was local recurrence and further surgery was performed. The patient developed pulmonary and central nervous system metastases. Pan-TRK antibody staining was positive and genomic profiling with next-generation sequencing confirmed a TPM3–NTRK1 gene fusion. The patient started treatment with larotrectinib in February 2019, with a durable response, including a clear reduction in brain metastases. Research on novel gene fusions and molecular testing to direct the use of targeted therapy should be encouraged, especially in refractory solid tumors.