Introduction

Diffuse leptomeningeal glioneuronal tumors (DL-GNT) were described in a case report by Yamamoto et al. [24] in 1996, following which Psarros et al. [20] reported a case of neurocytoma-like neoplasm of the thoracic spine with diffuse leptomeningeal dissemination. A few years later, Gardiman et al. [7] described these DL-GNTs in greater detail.

In addition to glioneuronal histology, diffuse leptomeningeal oligodendrogliomas or oligodendrogliosis have also been reported [4, 15, 17, 21]. Considering that these studies were published in the era before the concept of glioneuronal tumor emerged and that there is no specific immunomarker for oligodendroglial tumors yet, the tumors in these cases might have actually been neurocytoma-like leptomeningeal GNT [4, 15]. The tumors in the above-mentioned cases were characterized by diffuse leptomeningeal dissemination, neurocytoma-like, bland-looking histology, and aggressive clinical behavior. Gardiman et al. [8] reported 3 cases of DL-GNT with the following 5 distinct characteristics: (1) characteristic involvement of the basal cisterns and interhemispheric fissure; (2) thickened and enhanced leptomeninges (subarachnoid space); (3) wide leptomeningeal dissemination of the tumor, without a well-defined intraparenchymal mass; (4) bland-looking neurocytoma-like monotonous round tumor cells; and (5) glioneuronal differentiation. These characteristics and additional clinicopathological data of DL-GNT appear to be unique and it should be regarded as a novel entity. Here, we have reported three more cases of DL-GNTs, which showed typical clinicopathological features. The Institutional Review Board of Seoul National University Hospital (H-1305-040-485) approved this research. The IRB board waived informed consents.

Case summary

Clinical and radiological findings

All the cases of our DL-GNTs reported below involved male patients and their mean age was 32 years (11–66 years), who were treated in SNU hospital. The patients presented with seizures (n = 1) or headaches (n = 2) (Table 1). Radiology showed leptomeningeal thickening with enhancement and minor superficial parenchymal lesion on the contrast-enhanced T1-weighted image (T1WI) in all cases (Fig. 1). The tumor in each case located in the cerebellum (case #1), temporal lobe (case #2), and a wide area of the brainstem (from the brainstem to the suprasellar area), spinal cord and cauda equina (case #3). Neurosurgeons carried out subtotal resection (case #1), gross total resection (case #2), or biopsy of tumors and ventriculo-peritoneal shunt (case #3) (Table 1).

Table 1 Summary of clinical features
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Fig. 1
figure 1

a, b Contrast-enhanced T1WIs (case #1) revealed leptomeningeal enhancement at the surface of the brain stem, and nodular enhancement at the inferior cerebellar vermis, which suggested leptomeningeal seeding. c Contrast-enhanced T1WI (case #2) showed thick leptomeningeal enhancement at the right temporal lobe, which suggested leptomeningeal involvement. d, e Contrast-enhanced T1WI (case #3) showed thick leptomeningeal enhancement at the suprasellar and prepontine area, which suggested leptomeningeal involvement. f A sagittal contrast-enhanced T1WI (case #3) showed the diffuse thick enhancement along the spinal cord and cauda equina, which suggests the diffuse leptomeningeal involvement

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Pathological findings

Microscopically, all tumors grew along the leptomeninges. The cases #2 and #3 showed low-grade features but case #1 was high-grade tumor. The high-grade one (case #1) revealed a pseudo-papillary pattern of atypical glial cells with high mitotic rate and necrosis (Fig. 2), while two cases of low-grade ones were composed of bland-looking monotonous round shaped cells with clear cytoplasm (Fig. 3). In low-grade ones, mitotic rate was nearly absent and MIB-1 indices were low (1.3 and 3.9 %), but it was high (38.4 %) in case #1. All three patients were diffusely positive for synaptophysin and scatter positive for OLIG2 and NeuN, but all were negative for IDH-1 (H09) (Fig. 2; Table 2). GFAP was diffusely or partly positive in the tumor cells. Nestin was focal positive in all cases. On electron microscopic examination, all cases showed predominantly neuronal differentiation with synapses and synaptic vesicles, along with astrocytic differentiation with glial filaments. Ultrastructure of case #2 revealed numerous perikaryal and synaptic electron-dense core neurosecretory granules (Fig. 4).

Fig. 2
figure 2

a H&E section in case #1 mainly revealed the leptomeningeal tumor with superficial involvement of the cerebellar molecular layer. b High-power view shows sheets of monotonous rounded tumor cells with rounded nuclei and clear cytoplasm. c, d Double immunostatining of neurofilaments (brown) and olig2 (red) revealed positivity in the cytoplasmic processes and tumor cell nuclei, respectively, suggesting glioneuronal differentiation. d, e Tumor cells are robustly positive for GFAP and synaptophysin. (a H&E ×20, b H&E ×200, c GFAP ×400, c NF and Olig2 double immunostaining ×400, d GFAP ×400, e Synaptophysin ×400) (color figure online)

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Fig. 3
figure 3

a, b Leptomeningeal tumor composed of monotonous neurocyte-like tumor cells was also observed in case #2. c, d Case #3 showed perivascular accentuated distribution of monotonous neurocyte-like cells with neuropil background. Synaptophysin was diffusely positive in the background of tumor cells that are exclusively located in the leptomeningeal area (a H&E ×10, b H&E ×400, c H&E ×200, d synaptophysin ×250)

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Table 2 Primary antibodies and results of immunohistochemical stains
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Fig. 4
figure 4

a Ultrastructurally, the tumor cells of case #2 have oval to round nuclei and scanty to moderate amount of perikaryal cytoplasm, which contains numerous electron-dense core neurosecretory granules, abundant RER cisternae and mitochondria. b Surrounding the tumor cells, there are rich neuropils. Some of neuropils have many neurosecretory granules (uranyl acetate and lead citrate, a ×8,000, b ×7,000)

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Follow-up

The patient with the anaplastic tumor (case #1) died due to aggressive progression of the tumor despite of one cycle of chemoradiation therapy (Table 1). Case #3 had a persistent residual tumor because he underwent biopsy only and he was hopelessly discharged with respirator. The remaining alive patient (case #2) did not have tumor recurrence for 37-month follow-up period.

Discussion

Davila et al. [5] have reported 3 clinical settings for leptomeningeal gliomatosis, which are: concurrent extensive meningeal dissemination with recurrence of intracerebral gliomas (20–25 % of gliomas), fatal meningeal dissemination without recurrence of primary gliomas (3 %), and primary leptomeningeal gliomatosis (very rare). The primary leptomeningeal glioma/gliomatosis are well-known entities and histopathologically can be similar to astrocytic, oligodendroglial, or neuronal/glioneuronal tumors (Table 3) [1–3, 5, 6, 9–14, 16, 18, 19, 23]. They predominantly occur in children (mean age 18.45 years; range 3–49 years) (Table 3). Further, 73 % of the patients in the above-mentioned cases were aged less than 20 years, and there was a slight male dominance (M:F, 6:5). They often involve a wide area of the cerebrum or the cerebellum; however, most cases were of low-grade glioneuronal tumors, which had been variously diagnosed as oligodendroglioma, astrocytoma, or glioblastoma (Table 3). The prognosis was poor (average survival, 22 months), and 73 % (8/11) of the patients died. Of note, 63 % (5/8) of the patients died within 9 months after diagnosis. By definition, primary DL-GNT should have diffuse leptomeningeal tumor without significant parenchymal involvement and/or previous parenchymal tumor. However, some cases involved superficial parenchyma or Virchow–Robin spaces [5, 8, 12]. DL-GNT might be a novel brain tumor because it has 5 clinicopathological characteristics: (1) involvement of a wide area of the leptomeninges, particularly the basal cisterns and interhemispheric fissure; (2) bland-looking oligodendroglioma or neurocytoma-like monotonous histology; (3) immunohistochemical glioneuronal differentiation; (4) common occurrence in children; and (5) aggressive behavior (Table 3). Thickened and enhanced meninges on MRI are also characteristic findings.

Table 3 The summary of previously reported diffuse leptomeningeal gliomatosis and DL-GNTs
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Yamamoto et al. [24] described a case of multifocal neurocytoma/gangliocytoma with extensive leptomeningeal dissemination in 1996, and Gardiman et al. [8] reported four cases of diffuse leptomeningeal GNTs in children including one case of anaplastic one. The findings of those cases were consistent with our findings, especially the neurocytic histology. Among our cases, the case #3 was the most typical case, which involved the wide basal brain surface of the cerebrum, cerebellum, and spinal cord of the patient.

In our series, two cases revealed bland-looking histology, but one case showed a high-grade feature (case #1). It had a high mitotic rate (20/10HPF) and a high MIB-1 labeling index (38.4 %), suggesting malignant GNT. The differential diagnosis of this case included anaplastic clear cell ependymoma and anaplastic papillary glioneuronal tumor. We were able to rule out the possibility of an ependymoma, because immunohistochemically, this tumor did not show dot-like positivity for EMA and/or CD99. Moreover, electron microscopic examination did not reveal any ependymal features. To our knowledge, only leptomeningeal involvement has not been reported in any ependymoma. In addition, PGNT do not typically show primarily leptomeningeal development and/or leptomeningeal dissemination. Our case of high-grade DL-GNT (case #1) was similar to the Gardiman et al.’s high-grade DL-GNT. The existence of high-grade DL-GNT had been pointed out by Rossi et al. [22].

In contrast to low-grade histopathological features of usual DL-GNTs, they often showed aggressive biology like our case #3. Our case #3 showed wide leptomeningeal involvement of suprasella to brainstem and spinal cord, which could not be surgically removed entirely. The patient showed respiratory difficulty and was discharged to the nursing home with ventilator in a poor recovery state, 1 month after operation.

The main differential diagnosis of the DL-GNTs is primary DL-glioma/gliomatosis, which also can be either high- or low-grade glioma [1, 13, 18, 19]. They should be differentiated histomorphologically and/or immunohistochemically and ultrastructurally. DL-GNT should be positive for both neuronal and glial markers, while DL-glioma/gliomatosis is negative for neuronal markers.

Conclusion

Here, we have reported three cases of DL-GNTs, which showed particular clinicopathological and radiological features, specifically, plaque-like dural thickening by the tumor involvement, with minor parenchymal involvement, as well as a neurocytoma-like bland-looking histology with immunohistochemical glioneuronal differentiation. Even though they are histologically benign, they can show aggressive behavior due to tendency of involvement of wide area of leptomeninges and common development around the brainstem, resulting in difficulty in surgical intervention. Further clinicopathological data with molecular genetic study are required for establishing DL-GNT as a unique entity.