Myxoid glioneuronal tumor, PDGFRA p.K385-mutant: clinical, radiologic, and histopathologic features

Abstract

"Myxoid glioneuronal tumor, PDGFRA p.K385-mutant" is a recently described tumor entity of the central nervous system with a predilection for origin in the septum pellucidum and a defining dinucleotide mutation at codon 385 of the PDGFRA oncogene replacing lysine with either leucine or isoleucine (p.K385L/I). Clinical outcomes and optimal treatment for this new tumor entity have yet to be defined. Here, we report a comprehensive clinical, radiologic, and histopathologic assessment of eight cases. In addition to its stereotypic location in the septum pellucidum, we identify that this tumor can also occur in the corpus callosum and periventricular white matter of the lateral ventricle. Tumors centered in the septum pellucidum uniformly were associated with obstructive hydrocephalus, whereas tumors centered in the corpus callosum and periventricular white matter did not demonstrate hydrocephalus. While multiple patients were found to have ventricular dissemination or local recurrence/progression, all patients in this series remain alive at last clinical follow-up despite only biopsy or subtotal resection without adjuvant therapy in most cases. Our study further supports "myxoid glioneuronal tumor, PDGFRA p.K385-mutant" as a distinct CNS tumor entity and expands the spectrum of clinicopathologic and radiologic features of this neoplasm.

Keywords: PDGFRA; DNT-like tumor of the septum pellucidum; corpus callosum; dysembryoplastic neuroepithelial tumor (DNT); lateral ventricle; molecular neuro-oncology; molecular neuropathology; myxoid glioneuronal tumor; periventricular white matter; platelet-derived growth factor receptor alpha; septal DNT; septum pellucidum.

Figure 1

Myxoid glioneuronal tumor, PDGFRA p.K385‐mutant, can also arise in the corpus callosum, in addition to its stereotypic location in the septum pellucidum. Pre‐operative magnetic resonance images for patients MGNT #4 (8‐year‐old female) and MGNT #6 (6‐year‐old female) showing a well‐circumscribed, T2/FLAIR‐hyperintense mass lesion centered in the genu of the corpus callosum.

Figure 2

Myxoid glioneuronal tumor, PDGFRA p.K385‐mutant, can be associated with ventricular dissemination. Pre‐operative magnetic resonance images (left) for patient MGNT #2 (31‐year‐old male) showing a primary mass centered in the septum pellucidum with associated ventricular dissemination consisting of nodular studding along the ventricular surfaces. Pre‐operative magnetic resonance images (right) for patient MGNT #8 (14‐year‐old male) showing a primary mass centered in the periventricular white matter of the left lateral ventricle, as well as a solitary nodular focus of presumed ventricular dissemination in the inferior horn of the left lateral ventricle.

Figure 3

Histologic features of the eight myxoid glioneuronal tumors, PDGFRA p.K385‐mutant. Shown are representative hematoxylin and eosin stained sections from cases MGNT #1‐8. All cases demonstrate a low cellularity proliferation of oligodendrocyte‐like cells with monotonous round to oval nuclei, small nucleoli, and scant to moderate eosinophilic cytoplasm within a mucin‐rich stroma. Scattered floating neurons and neurocytic rosettes are occasionally seen. Mitotic activity is uniformly inconspicuous, while neither necrosis nor glomeruloid microvascular proliferation are present in any of the tumors.

Figure 4

Immunohistochemical features of myxoid glioneuronal tumor, PDGFRA p.K385‐mutant. Shown are representative immunohistochemical stains from case MGNT #7 demonstrating cytoplasmic positivity for MAP2 in most tumor cells, along with diffuse nuclear positivity for OLIG2 and SOX10. CD34 staining is limited to endothelial cells. The Ki67 labeling is low.

Figure 5

PDGFRA mutations identified in the eight myxoid glioneuronal tumors, PDGFRA p.K385‐mutant. A. Diagram of the human PDGFRA protein with the location of the recurrent p.K385L/I mutations within the extracellular ligand‐binding domain. UniProt ID P16234. B. Snapshots from the Integrative Genome Viewer showing sequencing reads containing a dinucleotide substitution at codon 385 of the PDGFRA gene in all 8 cases causing a lysine to leucine or isoleucine substitution (p.K385L/I). RefSeq transcript NM_006206.

Figure 6

Clinical timeline for patient MGNT #1, a 27‐year‐old man who presented with cognitive disturbance. Following gross total resection of a tumor centered in the septum pellucidum without administration of adjuvant therapy, he subsequently experienced local disease recurrence at 2 years after diagnosis. He is currently alive at 6.2 years following a second resection in the absence of any radiation or chemotherapy.

Figure 7

Clinical timeline for patient MGNT #3, a 13‐year‐old boy who presented with orbital cellulitis and was found to have an incidental mass lesion centered in the septum pellucidum. Following subtotal resection without administration of adjuvant therapy, he was found to have local disease progression as well as disseminated disease in the posterior horns of the lateral ventricles at 1.3 years after diagnosis. He is currently alive at 4.2 years following a second subtotal resection in the absence of any radiation or chemotherapy.

Figure 8

Clinical timeline for patient MGNT #5, a 65‐year‐old woman who presented with headaches and cognitive impairment. Following gross total resection of a tumor centered in the septum pellucidum without administration of adjuvant therapy, she subsequently experienced local disease recurrence at 1.2 years after diagnosis. She is currently alive at 12.1 years following multiple courses of chemotherapy with temozolomide and lomustine (CCNU), as well as fractionated external beam radiation therapy.