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Primary Intracranial Spindle Cell Sarcoma, DICER1-Mutant, with MDM2 Amplification Diagnosed on the Basis of Extensive
Takahide Nejo1, Shunsaku Takayanagi1, Shota Tanaka1
1Department of Neurosurgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Abstract:
Primary intracranial spindle cell sarcoma is an extremely rare mesenchymal tumor, the molecular pathogenesis of which is poorly understood. Because of the lack of specific markers, diagnosis sometimes relies on ruling out all possible differential diagnoses, often making it difficult to reach a definitive diagnosis. In this case study, we report a 69 year-old female patient for whom the integration of multi-layered molecular analyses contributed to making the diagnosis. The disease exhibited aggressive clinical behavior, requiring two sequential surgeries because of rapid regrowth within a short period. Primary and recurrent tumors exhibited similar histological features, in which spindle-shaped cells arranged in interlacing fascicles without any specific architectures, implicating sarcomatous tumors. In immunohistochemistry testing, tumor cells were immunopositive for vimentin but lacked any specific findings that contribute to narrowing down the differential diagnoses. Seeking further diagnostic clues, we performed DNA methylation-based analysis. The copy number analysis revealed MDM2 gene amplification and loss of heterozygosity of 22q. Moreover, dimension reduction clustering analysis implicated a methylation pattern comparable to aggressive types of sarcomas. In addition, an in-house next-generation sequencing panel ("Todai-OncoPanel") analysis identified somatic mutations in DICER1, NF2, and ATRX genes. Taken all together, we finally made the diagnosis of primary intracranial spindle cell sarcoma, DICER1-mutant, with MDM2 gene amplification. This case report suggests that even for the tumors with insufficient morphological and immuno-histological diagnostic clues, integration of multi-layered molecular analyses can contribute to making the diagnoses as well as to understanding the rare tumors by elucidating unexpected genetic and epigenetic features.
Insights
Diagnosing rare intracranial spindle cell sarcoma is challenging. Multi-layered molecular analysis, including DNA methylation and next-generation sequencing, identified key genetic mutations (DICER1, NF2, ATRX) and MDM2 amplification, aiding definitive diagnosis.
Area of Science:
- Neuro-oncology
- Molecular Pathology
- Genomics
Background:
- Primary intracranial spindle cell sarcoma is a rare mesenchymal tumor with poorly understood molecular pathogenesis.
- Diagnostic challenges arise from a lack of specific markers, often necessitating extensive differential diagnoses.
Observation:
- A 69-year-old female presented with an aggressive intracranial spindle cell sarcoma.
- Histopathology showed spindle cells without specific architecture; immunohistochemistry was non-specific (vimentin positive).
- Tumor exhibited rapid regrowth, requiring two surgeries.
Findings:
- DNA methylation analysis revealed MDM2 gene amplification and 22q loss of heterozygosity.
- Clustering analysis indicated a methylation pattern similar to aggressive sarcomas.
- Next-generation sequencing identified somatic mutations in DICER1, NF2, and ATRX genes.
Implications:
- Integrated molecular analyses are crucial for diagnosing rare tumors lacking clear histological or immunohistochemical features.
- This case establishes a DICER1-mutant primary intracranial spindle cell sarcoma with MDM2 amplification.
- Elucidating genetic and epigenetic features advances understanding of rare tumor biology.
