Recurrent oligodendroglioma with changed 1p/19q status

Abstract

We report a case of oligodendroglioma that had consistent histopathological features as well as a distinct change in 1p/19q status in the second recurrence, after temozolomide chemotherapy and radiotherapy. The first tumor recurrence had oligodendroglial morphology, IDH1 R132H and TERT promoter mutations, and 1p/19q codeletion detected by fluorescent in situ hybridization (FISH). Copy number analysis, assessed by next-generation sequencing, confirmed 1p/19q codeletion, and disclosed loss of heterozygosity (LOH) of chromosomes 4 and 9 and chromosome 11 gain. The second recurrence featured not only oligodendroglial morphology but also the appearance of admixed multinucleated giant cells or neoplastic cells having oval nuclei and mitoses and showing microvascular proliferation; it maintained IDH1 R132H and TERT promoter mutations, acquired TP53 mutation, and showed 19q LOH, but disomic 1p, detected by FISH. Copy number analysis depicted LOH of chromosomes 3p, 13, and 19q, 1p partial deletion (1p chr1p34.2-p11), and gain of chromosomes 2p25.3-p24.1, 8q12.2-q24.3, and 11q13.3-q25. B-allele frequency analysis of polymorphic sites disclosed copy-neutral LOH at 1p36.33-p34.2, supporting the initial deletion of 1p, followed by reduplication of 1p36.33-p34.2 alone. These findings suggest that the two tumor recurrences might have originated from an initial neoplastic clone, featuring 1p/19q codeletion and IDH1 and TERT promoter mutations, and have independently acquired other copy number alterations. The reduplication of chromosome 1p might be the result of temozolomide treatment, and gave rise to false negative 1p deletion detected by FISH. The possibility of 1p copy-neutral LOH should be considered in recurrent oligodendrogliomas with altered 1p/19q status detected by FISH.

Keywords: H3K27me3; IDH; TP53; oligodendroglioma; tumor mutational burden.

Fig 1

Findings of the first recurrent tumor on histology (HE), immunohistochemistry (IDH1, ATRX, and p53), and FISH (1p and 19q). The neoplastic cells have round, slightly atypical, nuclei and perinuclear clear halo and show brisk mitotic activity and microvascular proliferation. These histological features are consistent with anaplastic oligodendroglioma. The tumor cells are immunoreactive for IDH1 R132H, show retained TRX immunoreactivity, and are scatteredly immunoreactive for p53. FISH reveals 1p/19q codeletion. While green signals indicate 1q and 19, red signals indicate 1p and 19q. Scale bars: 100 μm (IDH1, ATRX), 50 μm (HE, p53, 1p, 19q).

Fig 2

Findings of the second recurrent tumor on histology (HE), immunohistochemistry (IDH1, ATRX, and p53), and FISH (1p and 19q). The neoplastic cells have round or oval, markedly atypical nuclei show brisk mitotic activity and microvascular proliferation, and are intermingled with nultinucleated giant cells. These observations pose a differential diagnosis between astrocytoma and anaplastic oligodendroglioma. The tumor cells are immunoreactive for IDH1 R132H, show retained TRX immunoreactivity, and are negative for p53. FISH reveals disomic 1p and 19q loss of heterozygosity. While green signals indicate 1q and 19, red signals indicate 1p and 19q. Scale bars: 100 μm (insert, ATRX, p53), 50 μm (HE, IDH1, 1p, 19q).

Fig 3

Immunohistochemical findings for H3K27me3 in the first (A) and second (B) recurrent tumors. In both the tumors, nuclear immunoreactivity is lost in tumor cells and in contrast retained in non‐neoplastic glial cells and endothelial cells. Scale bars: 200 μm (A, B).

Fig 4

Chromosomal alterations detected by copy number variation (CNV) analysis in two oligodendroglioma recurrences. Chromosomal alterations are inferred from NGS. Targeted regions include coding exons of 174 genes and a whole‐chromosome backbone at the resolution of 1 megabase.