June 2023 – Neuropathology

Oligosarcoma, IDH-mutant and 1p19q co-deleted.

Histologically shown is brain parenchyma with a high-grade neoplasm composed of spindle cells arranged in intersecting fascicles. The pericellular reticulin deposition and loss of immunohistochemical glial markers (OLIG2 and GFAP) supports a sarcomatous component of the tumor (Fig. 4). Focally, regions of tumor showed a classic oligodendroglial morphology characterized by tumor cells with round nuclei and with perinuclear clearing (Fig. 3). This subset of tumor cells retained expression of OLIG2 and GFAP, and likely represents the precursor glial tumor to the sarcomatous component. The tumor was positive for mutant IDH1 and retained expression of ATRX. The tumor showed elevated mitotic activity, necrosis, and microvascular proliferation, which are features of a high-grade CNS neoplasm (Fig. 2). Further additional molecular studies were performed. Chromosomal microarray identified the co-deletion of the whole arms of 1p and 19q, and homozygous loss of CDKN2A and CDKN2B (Fig 6). Next-generation sequencing confirmed the presence of a IDH1 mutation, as well as a TERT promoter, NF1, and NF2 mutation. Whole genome methylation analysis performed at the Pathology Laboratory, National Cancer Institute, indicated a methylation profile of diffuse glioma, IDH-mutant and 1p19q codeleted/Oligosarcoma, IDH-mutant. 

Oligosarcoma, IDH-mutant is rare CNS diffuse glioma that can be diagnostically challenging. Oligosarcomas are most associated with oligodendroglioma but can occur in patients without a known history. Oligosarcomas are histopathologically characterized by an infiltrating spindle cell neoplasm demonstrating large degrees of sarcomatous or leiomyosarcomatous differentiation and abundant pericellular reticulin deposition. Studies support that the sarcomatous components of oligosarcomas represent a differentiated population of tumor cells, which is highlighted by the immunohistochemical loss of glial markers. The transformation of these tumor cells is further supported by immunoreactivity for smooth muscle actin which has been documented in a large proportion of oligosarcomas. Oligosarcoma shares several molecular features with oligodendroglioma, including the diagnostic IDH1/2 mutation, and frequently the 1p19q co-deletion. However, oligosarcomas appear to more frequently harbor molecular changes associated with overall worse outcomes in CNS tumors, including CDKN2A/B homozygous deletion and TERT promoter mutations.

Lastly, a recent study examining the tumor methylation profile of a large cohort of oligosarcomas shows these tumors form a distinct DNA methylation group. To date, the precise delineation between oligosarcoma and oligodogliomas remains unclear. While the definitive grading of the oligosarcoma is not well established, oligosarcomas overall have a poor clinical outcome and demonstrate aggressive behavior.

References

1. Louis, DN., et al. (2021). WHO Classification of Tumours Editorial Board. Central nervous system tumours, Lyon (France): International Agency for Research on Cancer.
2. Appay R, Dehais C, Maurage CA, et al. CDKN2A homozygous deletion is a strong adverse prognosis factor in diffuse malignant IDH-mutant gliomas. Neuro Oncol. 2019 Dec 17;21(12):1519-1528. doi:10.1093/neuonc/noz124.
3. Hiniker A, Hagenkord JM, Powers MP, Aghi MK, Prados MD, Perry A. Gliosarcoma arising from an oligodendroglioma (oligosarcoma). Clin Neuropathol. 2013 May-Jun;32(3):165-70. doi:10.5414/NP300577. 
4. Ren X, Jiang H, Cui X, et al. Co-polysomy of chromosome 1q and 19p predicts worse prognosis in 1p/19q codeleted oligodendroglial tumors: FISH analysis of 148 consecutive cases. Neuro Oncol. 2013 Sep;15(9):1244-50. doi:10.1093/neuonc/not092. 
5. Rodriguez FJ, Scheithauer BW, Jenkins R, et al. Gliosarcoma arising in oligodendroglial tumors ("oligosarcoma"): a clinicopathologic study. Am J Surg Pathol. 2007 Mar;31(3):351-62. doi: 10.1097/01.pas.0000213378.94547.ae.
6. Suwala AK, Felix M, Friedel D, et al. Oligosarcomas, IDH-mutant are distinct and aggressive. Acta Neuropathol. 2022 Feb;143(2):263-281. doi:10.1007/s00401-021-02395-z.