Papillary glioneuronal tumor (PGNT) is a low-grade biphasic tumor that is composed of glial fibrillary acidic protein (GFAP)-positive glial cells and synaptophysin-positive neurons. PGNT was first reported in 1998 by Komori [1], and it is recently identified in the World Health Organization (WHO) 2021 classification as a grade 1 mixed glial–neuronal neoplasm of young adult patients. In this report, we present a case of PGNT with the symptom of acute headache, which was difficult to distinguish from malignant brain tumors.

A 48-year-old right-handed woman noticed a severe headache the day before and consulted a doctor. Computed tomography (CT) scan revealed a cystic lesion with intralesional hemorrhage and calcification in the right occipital lobe (Figure 1A), and she was referred to our hospital and admitted for surgery. On admission, she was conscious with no motor paralysis and sensory disturbance, but neurological examination showed left homonymous hemianopsia. Head magnetic resonance imaging (MRI) scan revealed cystic and solid components with peritumoral brain edema, and these components were contrast-enhanced using a contrast medium (Figure 1B-C). In susceptibility-weighted imaging (SWI), a low-intensity lesion, possibly indicative of intratumoral hemorrhage, was extensively noted (Figure 1D) despite hypoperfusion in arterial spin labeling (ASL) MRI (Figure 1E). An increase in the Cho/NAA ratio was not observed using magnetic resonance spectroscopy (MRS, Figure 1F). Figure 1G shows amide proton transfer (APT) chemical exchange saturation transfer (CEST) imaging. The APT signal intensity in the solid component was approximately 2.5%. Based on the tumor contrast enhancement, peritumoral brain edema, and intratumoral hemorrhage, a malignant glioma or a metastatic brain tumor was suspected.

Figure 1: Preoperative CT and MRI imaging are shown. Plain CT (a) showed a cystic space-occupying lesion with hemorrhagic change and calcification in the right occipital lobe. T1-weighted imaging (b) and contrast-enhanced T1-weighted imaging (c) showed heterogeneously enhanced lesion that consisted of cystic and solid components. In susceptibility-weighted imaging (d), a low-intensity lesion, possibly indicative of intratumoral hemorrhage, was extensively noted. The findings of hyper-perfusion in ASL (e) and an elevated Cho/NAA ratio in MRS (f) were not observed. The solid component revealed a moderate increase in APT CEST imaging (g black arrow).

The patient underwent tumor removal in the prone position. As malignant glioma was strongly suspected, the cystic tumor and surrounding normal brain tissues were removed until the cerebral falx and cerebellar tentorium were visible on the median and caudal side, respectively (Figure 2A). The residual yellowish solid component adjacent to the ventricular wall emitted red fluorescence during intraoperative photodynamic testing (Figure 2B); this finding could easily be misdiagnosed as malignant glioma. The solid tumor was additionally detached from the ventricular wall to achieve gross total removal of the tumor. In addition, as rapid intraoperative diagnosis suggested a malignant glioma, the opened ventricle was closed and carmustine (BCNU) wafers were placed to complete the operation.

Figure 2: Intraoperative photographs are shown. The right occipital lobe tumor was resected until the cerebral falx (A black arrow) and cerebellar tentorium (A double black arrow) were visible on the median and caudal side, respectively. The residual deep-seated tumor with 5-ALA positive fluorescence (A double black arrowhead; B white arrowhead) was resected, and the posterior horn of the lateral ventricle (A black arrowhead) was opened.

The pathological examination revealed a predominant papillary pattern characterized by multiple layers of GFAP-positive glial cells lining markedly thickened hyalinized vessels (Figure 3A-C). In addition, synaptophysin-positive neurons were observed between the pseudopapillary structures (Figure 3B, 3D). Immunohistochemical examination revealed a high expression of CD34 (Figure 3E). The MIB-1 staining index was extremely low. Based on the histological findings above mentioned, a diagnosis of PGNT was achieved.

Figure 3: Photomicrographs (A H&E staining, original magnification ×100; B H&E staining, original magnification ×200; C GFAP staining, original magnification ×100; D synaptophysin staining, original magnification ×100; E CD34 staining, original magnification ×100) showed GFAP-positive glial cells lining hyalinized vessels and synaptophysin positive nerve cells in the GFAP-negative areas. Immunohistochemical examination revealed a high expression of CD34.

The patient was observed without postoperative chemo-radiotherapy, and at the 1-year follow-up, MRI revealed no obvious recurrent lesions (Figure 4).

Figure 4: Postoperative MRI 1 year after the surgery is shown. T1-weighted imaging (A) and contrast-enhanced T1-weighted imaging (B) showed no obvious recurrent lesion.

PGNT is characterized by the pseudopapillary proliferation of GFAP- and S100 protein-positive astrocytes and the proliferation of synaptophysin- and NeuN-positive neurons around hyalinized vessels [2]. According to the 2021 WHO classification of central nervous system tumors, PGNT is classified as a grade 1 tumor, and total resection is generally considered to be conducive to a favorable prognosis. The mean age of patients at the onset is relatively lower (26.9 ± 16.3 years), and the male-to-female ratio is 1.42:1 [3]. The most common site of occurrence of PGNT is the frontal lobe (32.1%), followed by the temporal (21.6%) and parietal (11.9%) lobes [3]. Overall, PGNT occurs near the cerebral ventricles in 78.4% of cases [4], suggesting a possible origin from the germinal zone of the subependymal plate [5]. Typical imaging findings include cystic and solid lesions that lack peritumoral edematous changes, with calcification in 25% of the cases [1]. The effects of contrast enhancement in the cystic and solid areas vary from case to case [11].

In the present case, the patient presented with signs of peritumoral cerebral edema and intratumoral hemorrhage, which led to the misdiagnosis of malignant brain tumors, including malignant glioma, malignant lymphoma, and metastatic brain tumor. There have been sporadic reports of PGNT cases with similar findings as follows. Myung et al. reported that 13.7% of cases presented moderate or advanced peritumoral edema [6]. In even rarer cases, intratumoral and intraventricular hemorrhage triggered the onset [7-9]. Given the high immunohistochemical expression of CD34 as shown in the present case, peritumoral edema and intratumoral hemorrhage in PGNT cases may result from intratumoral growth of hyalinized microvessels rather than increased feeding vessels surrounding the tumor. Although malignant brain tumors could not be completely ruled out given the possibility of decreased perfusion imaging due to intratumoral hemorrhage, PGNT should be included as one of the differential diagnoses in case that the tumor shows hemorrhagic change despite decreased perfusion in ASL-MRI.

To the best of our knowledge, this is the first report of APT-CEST MRI imaging in PGNT case. APT imaging, a subtype of CEST imaging, detects endogenous mobile proteins and peptides. Togao et al. reported that APT signal intensities in the high-grade (grade 3 and 4) gliomas were higher than in the low-grade (grade2) gliomas, and regarding differentiation between high- and low-grade gliomas, APT signal intensities provided excellent sensitivity (93%) and specificity (100%) with a cutoff value of 2.54% [1]. Although further research is warranted, a moderate APT signal intensity increase (approximately 2.5%) in the solid component as shown in the present case could also be useful for the differential diagnosis of PGNT from other malignant brain tumors.

Other than the MRI findings above mentioned, the present case could also have been misdiagnosed as a malignant brain tumor based on the following intraoperative findings: (1) the solid component emitted red fluorescence during the intraoperative photodynamic diagnosis, and (2) the results of the rapid intraoperative diagnosis using only one sample from one site indicated a malignant glioma. To the best of our knowledge, only one case of intraoperative fluorescence in PGNT has been reported in the relevant literature [10] therefore, the former finding was extremely rare. Additionally, Labrador et al. reported intraoperative fluorescence in other cases of benign brain tumors [11]. Based on these reports, it should be noted that photodynamic testing is not specific to malignant brain tumors. Regarding the latter finding, if PGNT had been predicted from the preoperative imaging findings mentioned above, an accurate rapid intraoperative diagnosis could have been achieved by using multiple pathological specimens, focusing on the presence of biphasic cell patterns composed of glial and nerve cells.

We reported a case of PGNT with the symptom of acute headache, which was difficult to distinguish pre- and intra-operatively from malignant brain tumors because of peritumoral brain edema, intratumoral hemorrhage, and intraoperative fluorescence staining. Although further research is warranted, hemorrhagic change despite decreased perfusion in ASL-MRI and moderate APT signal intensity increase in the solid component could be useful for the differential diagnosis of PGNT from other malignant brain tumors.

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