Malignant Bone-Forming Neoplasm With NIPBL::BEND2 Fusion

Area of Science:

• Orthopedic Oncology
• Skeletal Pathology
• Molecular Diagnostics

Background:

• Conventional high-grade osteosarcomas present with aggressive features, but rare variants exhibit unusual histology, necessitating molecular confirmation.
• Sclerosing or osteoblastoma-like osteosarcomas can be diagnostically challenging due to non-specific histopathology.
• Accurate diagnosis is critical for appropriate management and prognosis of bone tumors.

Purpose of the Study:

• To characterize an aggressive acral bone-forming tumor with unusual initial presentation and histopathology.
• To identify the molecular drivers of the tumor and determine its precise classification.
• To evaluate the clinical behavior and treatment response of this rare osteosarcoma subtype.

Main Methods:

• Histopathological examination of tumor biopsies and surgical resection specimens.
• Immunohistochemistry for SATB2.
• RNA sequencing to identify gene fusions (NIPBL::BEND2).
• In situ hybridization for FGF23.
• DNA methylation profiling with unsupervised clustering and UMAP analysis.

Main Results:

• The tumor initially presented as a sclerotic lesion mimicking osteoblastoma but recurred aggressively.
• Histology evolved to high-grade osteosarcoma with lace-like osteoid deposition and uniform epithelioid cells.
• Molecular analysis revealed a NIPBL::BEND2 fusion, previously associated with phosphaturic mesenchymal tumor (PMT).
• DNA methylation profiling confirmed the tumor's classification as high-grade osteosarcoma, distinct from PMT.
• The patient achieved disease remission after chemotherapy following below-knee amputation.

Conclusions:

• The NIPBL::BEND2 fusion can occur in aggressive, high-grade osteosarcomas, expanding its known spectrum.
• Molecular profiling is essential for accurate diagnosis of challenging bone tumors, differentiating them from entities like PMT.
• This case highlights the potential for recurrent fusions in diverse bone tumor types and underscores the need for further research.