Diagnosis: Diffuse leptomeningeal glioneuronal tumor (DLGNT)


Test question (answer at the end):
What are the most common co-occurring genetic alterations present in diffuse leptomeningeal glioneuronal tumor (DLGNT)?

1. CDKN2A/B homozygous deletion and ATRX mutation
2. EGFR amplification and PTEN deletion
3. FGFR1 mutation and NF1 mutation
4. KIAA1549::BRAF fusion and chromosome 1p arm deletion

Discussion:
Diffuse leptomeningeal glioneuronal tumor (DLGNT) is a neoplasm of the central nervous system (CNS) that presents as disseminated disease of the leptomeninges or as a discrete spinal cord mass. Patients may present with signs of obstructive hydrocephalus or other neurological deficits. A majority of tumors involve the leptomeninges but may be intraparenchymal. Given the rare nature of this neoplasm, the incidence of DLGNT is unknown; however, there are limited epidemiological data suggesting that DLGNT is more common in the pediatric population with median age estimated to be ~5 years (Acta Neuropathol 2012;124:627, Acta Neuropathol 2018;136:239).

Histologically, these tumors demonstrate predominant glial morphology (Acta Neuropathol 2012;124:627, Am J Surg Pathol 2013;37:763). DLGNTs are low to moderately cellular and have neoplastic cells that appear oligodendroglial-like with round, monomorphic nuclei and perinuclear clearing. Rarely, anaplasia has been described. Neuronal differentiation occurs in a small subset of tumors and includes features ranging from neuropil islands to ganglionic differentiation. As these tumors occur in the leptomeninges, background desmoplastic or myxoid changes may be present. Eosinophilic granular bodies (EGBs) are found in a small subset of DLGNTs.

The immunophenotype of DLGNT encompasses variable glial and neuronal differentiation markers. For glial differentiation, the oligodendroglial-like tumor cells often express Olig2 (Acta Neuropathol 2012;124:627). Glial fibrillary acidic protein (GFAP) may be patchy or absent (Acta Neuropathol 2012;124:627, Am J Surg Pathol 2013;37:763). The neuronal marker synaptophysin is commonly seen in DLGNT. Other neuronal markers such as chromogranin and NeuN are less common, usually accompanying tumors with more neuronal or ganglionic differentiation. The neuroectodermal marker S100 is also common (Acta Neuropathol 2012;124:627, Am J Surg Pathol 2013;37:763). For specific mutations, immunohistochemistry for BRAF V600E may be positive in those cases with an associated mutation. Staining for IDH1 (R132H) is negative. ATRX has retained nuclear staining (Acta Neuropathol 2012;124:627, Am J Surg Pathol 2013;37:763).

The most frequent genetic alterations present in DLGNT are in the mitogen activated protein kinase (MAPK) pathway. The most common occurring MAPK alteration in DLGNT is the KIAA1549::BRAF fusion, which is also common in pilocytic astrocytomas (Acta Neuropathol 2015;129:609). Alternative MAPK alterations include BRAF V600E and FGFR1 mutations, among others. The KIAA1549::BRAF fusion in DLGNT often co-occurs with loss of chromosome arm 1p (Acta Neuropathol 2015;129:609). Furthermore, a small subset of DLGNT cases have been reported to have 1p/19q codeletion, like what is seen in oligodendroglioma (Am J Surg Pathol 2013;37:763). Unlike oligodendroglioma, DLGNT does not have mutations in IDH1/2. DLGNTs have distinct DNA methylation profiles. Two epigenetic subtypes have been proposed based on whole genome DNA methylation profiling, DLGNT methylation class (MC)-1 and DLGNT methylation class (MC)-2 (Acta Neuropathol 2018;136:239). DLGNT MC-2 tends to display loss of chromosome arm 1p with gain of chromosome arm 1q, while DLGNT MC-1 more often has 1p/19q-codeletion (Acta Neuropathol 2018;136:239).

There are not enough data for this rare CNS tumor type to assign a formal CNS World Health Organization (WHO) grade to DLGNT. It is thought that classical DLGNT cases may have more of a CNS WHO grade 2 behavior while those with high risk histologic or molecular features may behave more like CNS WHO grade 3. There are case reports of DLGNTs displaying high grade histologic features, such as elevated mitotic activity, increased Ki67 proliferative index, frank anaplasia, necrosis and microvascular proliferation (Hum Pathol 2017;70:105, Brain Tumor Pathol 2018;35:209, Am J Surg Pathol 2013;37:763). DLGNT MC-2 has been reported to have decreased overall and progression free survivals, although this has not been seen in all studies (Acta Neuropathol 2018;136:239, Acta Neuropathol 2022;144:1185). Gain of chromosome arm 1q has also shown to indicate decreased overall and progression free survivals, independent of methylation class (Acta Neuropathol 2022;144:1185).

Test question answer:
D. KIAA1549::BRAF fusion and chromosome 1p arm deletion. These concurrent alterations are common in diffuse leptomeningeal glioneuronal tumor (DLGNT). While KIAA1549::BRAF fusion is frequent in pilocytic astrocytoma, these usually do not have chromosome 1p arm deletion. DLGNTs can also have 1p/19q codeletion but do not have IDH mutations like oligodendroglioma. Answer A is incorrect because CDKN2A/B homozygous deletion with ATRX mutation is common in high grade astrocytoma with piloid features (HGAP). Answer B is incorrect because EGFR amplification and PTEN deletion are frequent in glioblastoma, IDH wildtype. Answer C is incorrect because concurrent FGFR1 mutation and NF1 mutation are characteristic of rosette forming glioneuronal tumor (RGNT).