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Angiocentric glioma: A report of nine new cases, including four with atypical histological features
1
Hai-Chun Ni, MD1,2, Shi-Yun Chen, MD1, Li Chen, MD1, De-Hong Lu, MD1, Yong-Juan Fu, MD1, Yue-Shan Piao, MD1
1
Department of Neuropathology, Xuanwu Hospital, Capital Medical University, Beijing, China 2 Department of Pathology, Central Hospital of Wuhan, Wuhan, China Current address for correspondence and reprint requests: Yue-Shan Piao, MD, Department of Neuropathology, Xuanwu Hospital, Capital Medical University, Chang Chun Street 45, Xicheng District, Beijing 100053, China. E-mail: [email protected] Tel.: +86-10-83198757 We have no conflict of interest. A short running title: Angiocentric glioma with atypical histological features
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/nan.12158 This article is protected by copyright. All rights reserved.
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Abstract Aims: Angiocentric glioma (AG) is a rare, slow-growing tumor of the central nervous system. It is often associated with refractory epilepsy and occurs most commonly in children and young adults. We herein report 9 cases of AG, including 4 with atypical histological findings. Methods: The clinical data and clinicopathological findings of 9 cases with AG histological features were described. Results: All 9 patients had a history of refractory epilepsy with a mean history of 4.4 years and a median age of 17.6 years at surgery. The AG lesions were located in the superficial cerebrocortical region. Histological examination of these cases revealed characteristic structural features of AG, including bipolar spindle-shaped cells with an angiocentric growth pattern. However, 4 cases also exhibited atypical histological features: 1 had astroblastoma-like characteristics, 2 had a distinct cystic region with an onion-like structure and myxoid changes, and the other one had a region involving many abnormal neurons reminiscent to ganglioglioma. All were positive for glial fibrillary acidic protein and vimentin. Eight cases were positive for epithelial membrane antigen (EMA), with a dot-like staining pattern. A diffuse D2-40 staining was visible in these cases, with 2 having similar staining pattern to EMA. All cases were immuno-negative for BRAF V600E and isocitrate dehydrogenase-1 R132H mutations. Conclusions: Our results demonstrate that atypical histological features can be present in AG. A collection of more cases and further molecular analyses are required to confirm our findings. Key words: Angiocentric glioma; Histology; Immunohistochemistry; EMA; D2-40
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INTRODUCTION
Angiocentric glioma (AG) is a rare type of low-grade tumor occurring mainly in
children and young adults (1). It was first reported in 2005 by Lellouch et al. (2) and
Wang et al. (3) and categorized as a distinct clinicopathological entity in the 2007 World Health Organization (WHO) Classification of Tumors of the Central Nervous System (4), where it is described as a “neuroepithelial tumor of uncertain origin,” similar to astroblastoma and chordoid glioma of the third ventricle. AG is often located in the supratentorial region and associated with intractable
epilepsy. Most AG cases exhibit similar magnetic resonance imaging (MRI) features, such as hyperintensity on T2-weighted (T2WI) and fluid-attenuated inversion recovery (FLAIR) images without contrast enhancement after gadolinium administration (2). The histopathological characteristics of AG include a strikingly perivascular growth pattern, monomorphous bipolar cells, and features of ependymal differentiation with dot-like staining for epithelial membrane antigen (EMA) (5). As AG is rare, studies focusing on the disease are limited. To date, approximately
65 AG cases have been reported in the literature. Almost all these cases exhibited characteristic features of AG. We herein report an additional 9 cases of AG with intractable epilepsy. Furthermore, we also reviewed relevant literature and discussed the histological and immunohistochemical features of this relatively new tumor entity.
MATERIALS AND METHODS
Patients
Patients with histological characteristics of AG presented to the Department of
Neuropathology, Xuanwu Hospital, Capital Medical University, from January 2007 to June 2013 were selected. Their clinical data (sex, age at onset and surgery), MRI examinations, and pathological findings were retrospectively reviewed. All included patients were followed up until June 2013. The study was conducted after receiving written informed consent from the patients. In addition, this study was approved by the Institutional Ethics Committee of Xuan Wu Hospital, the Capital Medical University. This article is protected by copyright. All rights reserved.
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Histopathology A standard procedure for processing surgical specimens from patients with
intractable epilepsy was followed (6). For all specimens, coronal sections were
obtained. Selected blocks were processed for embedding in paraffin wax and 4-µm-thick sections were cut and routinely stained with hematoxylin and eosin (H&E). Selected sections were also processed for immunohistochemical studies with the polymer horseradish peroxidase (HRP) detection system (Polink-1 HRP Broad Spectrum DAB Detection Kit; Golden Bridge International, Mukilteo, WA, USA). The following primary antibodies were used: glial fibrillary acidic protein (GFAP; Dako, Glostrup, Denmark; polyclonal, dilution 1:1000), vimentin (Zymed, San Francisco, CA, USA; monoclonal, dilution 1:200), EMA (Zymed; monoclonal, dilution 1:50), podoplanin (Zymed; monoclonal clone D2-40, dilution 1:50), isocitrate dehydrogenase-1 (IDH1) R132H (MBL Company, Japan; monoclonal clone HMab-1, dilution 1:200), CD34 (Zymed; monoclonal, clone QBEnd 10, dilution 1:50), neuronal nuclear antigen (NeuN; Chemicon, Temecula, CA, USA; monoclonal, dilution 1:4000), synaptophysin (Biogenics, San Ramon, CA, USA; monoclonal, dilution 1:50), microtubule-associated protein-2 (MAP-2; Zymed, monoclonal, dilution 1:200), BRAF V600E (Spring Bioscience, Pleasanton, CA, USA; monoclonal clone VE1, dilution 1:50), and Ki-67 (MIB-1; Labvision, Fremont, CA, USA; monoclonal, dilution 1:50).
RESULTS
Patients
From January 2007 to June 2013, we identified 9 patients (5 men and 4 women)
with histological features of AG. Patient clinical data are summarized in Table 1. The patients’ median age at surgery was 17.6 years (range, 5–30 years), and they had a mean history of pre-surgical epilepsy of 4.4 years (range, 0.3–16 years). Among these,
8 cases were available for follow-up. No adjuvant chemotherapy or radiotherapy was administered following surgery. None of the 8 cases experienced seizure attacks or This article is protected by copyright. All rights reserved.
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tumor recurrence in during the follow-up period.
Imaging findings MRI of each patient revealed a well-defined mass in the superficial
cerebrocortical region, including 4 cases in the frontal lobe, 3 in the parietal lobe, and 2 in the temporal lobe. The masses appeared hypointense on T1WI, hyperintense on T2WI and FLAIR, but were non-enhanced after gadolinium contrast injection in all cases (Fig. 1a-f). In cases 6 and 8, the masses had a cystic appearance (Fig. 1g-i).
Histological and immunohistochemical findings Histological examination of the 9 cases revealed typical AG features.
Macroscopically, a tan-gray mass and a blurred cortex-white matter junction were observed in most cases (Fig. 2a). Microscopically, spindle-shaped cells were observed in angiocentric arrangements with circumferential, radial, or longitudinal alignments to both large and small vessels in the cortex and the subcortical white matter in all cases (Fig. 2b-e). The tumor cells appeared monomorphous, bipolar with uniform elongated blind nuclei, minimal cytoplasm, fine stippled chromatin, and inconspicuous nucleoli (Fig. 2f). Elongated cells were also observed orienting perpendicular to the cortical surface, forming a palisade in 6 cases (Fig. 2g). There were also juxtaposed areas of spindle-shaped cells arranged in a fascicular growth pattern, which appeared to be schwannoma-like in 7 cases (Fig. 2h). Entrapped single neurons were often identified within the tumor tissue (Fig. 2i). Adjacent focal cortical dysplasia (FCD) was observed in 6 cases with sufficient tissue for evaluation, and all were classified as FCD IIIb lesions according to the International League against Epilepsy updated category of FCD published in 2011 (7). These lesions with cortical radial and/or tangential abnormalities and cytoarchitectural composition (Fig. 3b-g) were adjacent yet separate from the tumors. No malignant features such as mitotic activity, vascular proliferation, or necrosis were observed in any cases. Microcalcification was observed around the tumor cells only in case 4. The immunohistochemical results are summarized in Table 2. In all 9 cases, tumor This article is protected by copyright. All rights reserved.
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cells were positive for GFAP (Fig. 4a) and vimentin (Fig. 4b), but negative for NeuN, except for neurons in some areas of case 9. Scattered tumor cells exhibited a distinct perinuclear dot-like staining pattern for EMA in 8 cases (Fig. 4c), whereas the other case was EMA-negative. A diffuse D2-40 staining was observed in 9 cases (Fig. 4d), with 2 cases displaying a dot-like staining pattern similar to that of EMA (Fig. 4e). All cases were negative for IDH1 R132H (Fig. 4f) and BRAF V600E. The tumor cells were negative for CD34 with the staining only observable for the blood vessels’ endothelial cells. In all cases, the tumor cells were found to have a low proliferative rate, with a Ki-67 labeling index of 1–5%. In addition to the characteristic AG features, 4 cases also had atypical histological
findings. In case 4, there was a region where unipolar tumor cells with columnar cytoplasm formed a typical astroblastoma-like structure (Fig. 5a-c). These tumor cells with stout processes and distinct cell borders aligned radially along the blood vessels (Fig. 5b-c). They also appeared differently from the spindle-shaped cells in other AG regions of the same case. Although a transitional region with elongated cells arranged in a fascicular and schwannoma-like pattern was present, no other astroblastoma-like feature such as vascular sclerosis or hyalinization was observed. Additionally, Ki-67 results indicated a low labeling index in the astroblastoma-like region. A large cyst with shrinkage of the cortices and gelatinous appearance of the
subcortical white matter was macroscopically visible in case 6 (Fig. 5d). Furthermore, a large cystic pattern and many microcystic formations inside and around the tumor were observable via microscopic examination (Fig. 5e). Typical AG histological features were observed within the cyst, including many bipolar spindle-shaped cells aligned radially or longitudinally along the parenchymal blood vessels (Fig. 5f). Similarly, cystic and microcystic formations were also observed in case 8. However,
part of the tumor contained bipolar, spindle-shaped cells forming an onion-like structure (Fig. 5g, h). Additionally, myxoid changes were noted in the cystic and onion-like structure (Fig. 5i). In case 9, a typical AG structure was observed with many abnormal neurons in the
tumor and adjacent cortex (Fig. 6a, b). These abnormal neurons appeared similar to This article is protected by copyright. All rights reserved.
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the “dysplastic neurons” often observed in a ganglioglioma (GG). They were ganglion-like, with vesicular nuclei and prominent nucleoli. Furthermore, perimembranous aggregated Nissl substance and occasional double-nucleus neurons were also observed. In addition to these morphological features, the neurons were abnormally distributed. The abnormal neurons were often identified within the tumor tissue of the AG lesion (Fig. 6f) with a progressive increase in numbers from the AG center to the transitional region and subsequently, the covering cortex (Fig. 6e–h). They were immunoreactive for the neuronal marker MAP-2 (Fig. 6d) and synaptophysin (Fig. 6e), but negative for CD34 and BRAF V600E.
DISCUSSION
Our cases presented various histological features of AG, astroblastoma-like feature,
distinct large cystic region with an onion-like structure, cystic and microcystic formations, and many abnormal neurons reminiscent to ganglioglioma (GG). A review of 65 reported AG cases (Tab. 3) suggested that the disease predominantly
occurred in children and young adults, with a median age of 16.0 ± 14.3 years (range, 2–70 years) at the time of surgical treatment. The male-to-female ratio was
approximately 1.5:1 (39/26). Clinical features were available for 59 cases, and 52 (88%) of these patients presented with intractable epilepsy. The majority of AG cases have similar MRI features such as hyperintensity on
T2WI and FLAIR as well as no contrast enhancement after gadolinium administration (2). However, T1WI results are less consistent, ranging from hypo- to hyperintense. Several cases showed subtle or mild enhancement after gadolinium administration (8-13). Three patients have shown cystic changes (12, 14, 15) and 2 have shown calcification (5, 16) on MRI. The main histopathological feature of AG is an angiocentric growth pattern of
bipolar spindle cells with ependymal features. In some cases, elongated cells arranged in schwannoma-like nodules or occasional round epithelioid cells in a nest-and-sheet arrangement are also observed (2–5). Besides these common histopathological This article is protected by copyright. All rights reserved.
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features,
other
atypical
findings
have
been
reported
in
AG,
including
calcifications/microcalcifications (7/65 cases, 11%) (2, 9, 12, 17–19) and microcystic/cystic changes (9/65 cases, 14%) (2, 3, 10, 19 ， 20). Furthermore, Buccoliero et al. described tumor cells embedded in a mucoid matrix and some microcalcifications in an AG case (12). Lu et al. reported the case of a 15-year-old boy involving a tumor with 2 distinct appearances, including AG characteristics and glioblastoma-like features (11). Recently, Miyata et al. suggested a rare but distinct clinicopathological subset of AG characterized by adult onset, mesial temporal lobe localization, and epithelioid cell-predominant histology (15). Based on the above-mentioned studies and the 2007 WHO classification, all of the
9 cases in this report fitted with an AG diagnosis. Interestingly, atypical histological findings were also observed in 4 cases, including an astroblastoma-like structure in 1 case, cystic and onion-like structures with myxoid changes in 2 cases, and abnormal neurons in another case. Astroblastoma-like structures are very rare in AG with only 1 case previously reported by Wang et al. (3). Additionally, Bonnin et al. also described perivascular cells with stout processes and distinct cell borders creating perivascular formations of astroblastoma type in some areas (21). Astroblastoma is a rare and controversial glial neoplasm that has not been universally accepted as a distinct entity. Astroblastoma and AG are of uncertain histogenesis and occur more frequently in children and young adults. Both of them present as superficial, cortical-based tumors with a distinct angiocentric growth pattern and GFAP expression. Therefore, to distinguish between AG and astroblastoma is challenging, particularly given the overlap between the 2 tumor types. However, to our knowledge, astroblastoma has never been reported with monomorphous and bipolar spindle-shaped cells as seen in AG. Thus, the tumor in our case was best diagnosed as an AG with an astroblastoma-like structure. In cases 6 and 8, a large cystic pattern and many microcystic formations inside and
around the tumors were observed with the former apparent in both imaging findings and gross examinations. Such a cystic pattern is more commonly observed macroscopically in scar tissue, but very rarely in AG. Of the 65 cases reported in the
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literature, only 3 cases exhibited cystic changes on imaging (12, 14, 15), and 9 cases had microcystic or large cystic patterns identified via histopathological studies (2, 3, 10, 19, 20). Lellouch et al. (2) reported 10 AG cases, including 3 with a microcystic pattern with 1 having a large cystic cavity. Liu et al. (20) also reported microcystic formation within the tumor in their case. Hu et al. (10) speculated that the cystic pattern in their case might be attributed to previous tumor hemorrhage. However, tumor hemorrhages were not observed in our cases. In case 8, besides the cystic pattern, part of the tumor region contained bipolar,
spindle-shaped cells arranged in an onion-like manner with myxoid changes observable in the cystic and onion-like structures. Such an onion-like structure with myxoid changes has not been reported in AG. The pattern of bipolar, spindle-shaped cells orienting towards the vessels and myxoid changes within the lesion resemble features of pilomyxoid astrocytoma (PMA) (22). However, the tumor cells were immunoreactive for EMA in this case, whereas EMA staining is often absent in PMA. Moreover, the cystic pattern was observable in imaging studies, gross examinations, and histopathological analysis, especially in the case with an onion-like structure and myxoid changes. Such observations have not been reported previously in the literature. A typical AG structure mixed with abnormal neurons was observed in case 9. GG,
the most common low-grade glioneuronal tumor, is often associated with refractory epilepsy (23). Except for the neoplastic glial element, the most significant feature of GG is the ganglion-like neurons, which was difficult to distinguish from the abnormal neurons in our case. However, other evidences of GG such as Rosenthal fibers or lymphocytes infiltration were not detectable in this case. Although some GG cases are negative for CD34, the stem cell marker is reportedly helpful for the disease identification (24). Additionally, BRAF V600E mutation can be detected in
approximately 50% of all GG cases (25). However, the abnormal neurons in our case, which we preferably defined as “entrapped neurons”, were negative for both CD34 and BRAF V600E. Furthermore, many infiltrative gliomas are diagnosed as GG because the differences between entrapped distorting and dysplastic neurons are This article is protected by copyright. All rights reserved.
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difficult to identify (25, 26). Indeed, many authors have considered the nerve cells interspersed within the tumor tissue in AG, which lacks neoplastic or dysplastic features, as preexisting neurons of the cerebral cortex diffusely infiltrated by the tumor (3, 5, 8, 9, 18). However, the neurons in this case presented in much greater abundance than previously reported, exhibiting some dysplastic features. Therefore, a collection of more cases and further molecular analyses are warranted to confirm whether such abnormal neurons resulted from an acquired dysplasia secondary to the principle lesion development (7). Similar to previously reported results, the tumor cells in these 9 AG cases were
immunoreactive for GFAP and vimentin, but negative for NeuN and IDH1 R132H. Ependymomatous features are frequently associated with a dot-like microlumen-type cytoplasmic staining for EMA. Of 52 cases available in the literature, dot-like cytoplasmic immunoreactivity for EMA was found in 48 cases (2, 3, 5, 9, 11-16, 20, 27-33). The other 4 cases were negative for EMA (8, 10, 18). However, the functional role of EMA expression in AG remains to be elucidated. We particularly believe that most AG cases might have ependymomatous features owing to the common expression of EMA in AG. The expression of D2-40 was also observed in our AG cases. D2-40 is a
monoclonal antibody originally raised against an unidentified protein derived from germ-cell tumors (34). D2-40 is considered a useful diagnostic marker for ependymal tumors, especially in combination with EMA (35). Preusser et al. (5) reported D2-40 expression in 8 AG cases. We also observed diffuse immunoreactivity for D2-40 in all of our cases, with 2 exhibiting a dot-like pattern similar to that of EMA staining. In accordance with a benign clinical behavior, AG characteristically exhibits a low
proliferative rate, with Ki-67 labeling indexes ranging from 1% to 5%. Most reports and WHO studies have indicated that AG is a slow-growing tumor with a low proliferative rate. The Ki-67 labeling indexes were lower than 5% in all of our cases. However, 7 AG cases have been previously reported with a high Ki-67 labeling index or malignant features (3, 11, 13, 15, 18, 26,28). In order to further explore the molecular pathogenesis and signature of AG, the
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expression of IDH1 R132H and BRAF V600E was assessed in our cases. Point
mutations of the IDHl gene have been described in almost 40% of grade II diffuse
gliomas but are not observable in grade I gliomas such as PA and GG (26). Activating mutations of BRAF are present at a high frequency in PA and GG yet less commonly in malignant gliomas. Thus, a combined analysis of IDH1 and BRAF can improve diagnostic accuracy in distinguishing grade I and malignant gliomas (25). A recent study utilizing high-resolution comparative genomic hybridization (CGH) points to genetically distinct subsets of diffuse low-grade gliomas suggested that tumors with complex chromosomal aberrations were often more aggressive (37). Moreover, another recent study involving patients with low-grade diffuse gliomas reported a
longer survival in those with 1p/19q +/- IDH1/2 mutations than those who with TP53 +/- IDH1/2 mutations (38). CGH has previously revealed a focal chromosomal loss involving 6q24-q25 as the only alteration in 1 of 8 cases with a high-resolution screen by array-CGH identifying a copy number gain at 11p11.2 containing the protein-tyrosine phosphatase receptor-type gene in 1 of 3 cases (25). In the few AG cases evaluated, loss of 1p/19q has not been shown (25). Among the 65 cases reported in the literature, only 3 series with 7 cases mentioned IDH1 and/or BRAF mutations in AG (11, 12, 31). In agreement with the above-mentioned reports, the expression of IHD1 R132H and BRAF V600E was not detected in any of our cases. To further study the molecular pathogenesis and signature of AG, a collection of more cases and further molecular analyses are definitely required.
CONCLUSIONS
We herein reported 9 cases with almost typical clinical, radiological, and
histological features of AG. Four cases also exhibited atypical histological features. One case had an astroblastoma-like feature; 2 had a distinct cystic region, with 1 having an onion-like structure and myxoid changes, and the remaining case presented with many abnormal neurons reminiscent to those in GG. Additional cases are required to confirm and extend the understanding of AG. Since the disease is rare, we
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believe that each new case should be carefully examined to clarify the biological behavior of this newly defined neoplasm.
Acknowledgments The author thanks Prof. Komori Takashi for his helpful opinion, and thanks Yang Hong, Zhao Li-hong and Wei Li-feng for their technical assistance. This work was supported by grants to Yue-Shan Piao from the Beijing Municipal Health Bureau “215 project”(No. 2011-3-095).
Author contributions. Collected clinical and imaging dada: H-C Ni and S-Y Chen. Analyzed the immunohistochemistry results: L Chen, D-H Lu, Y-J Fu and Y-S Piao. Contributed analysis diagnostic results and discussion: H-C Ni, S-Y Chen, L Chen, D-H Lu and Y-S Piao.Wrote the paper: H-C Ni, S-Y Chen and Y-S Piao.
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in
pleomorphic
xanthoastrocytoma,
ganglioglioma
and
extra-cerebellar pilocytic astrocytoma. Acta Neuropathol 2011; 121: 397–405.
37. Dahlback HS, Gorunova L, Brandal P, Scheie D, Helseth E, Meling TR, Heim S. Genomic aberrations in diffuse low-grade gliomas. Genes Chromosomes Cancer 2011;50: 409–420.
38. Kim YH, Nobusawa S, Mittelbronn M, Paulus W, Brokinkel B, Keyvani K, Sure U, Wrede K, Nakazato Y, Tanaka Y, Vital A, Mariani L, Stawski R, Watanabe T, De Girolami U, Kleihues P, Ohgaki H. Molecular classification of low-grade diffuse gliomas. The American journal of pathology 2010, 177: 2708-2714.
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Table 1 Main clinical findings of the present nine cases
Cas
Se
e
x
1
2
3
4
5
6
M
M
F
F
M
F
Epilep sy
Surge
Clinical
Followlocatio
onset
ry age
presentati
MRI
up
Outcome
n age
(yrs)
on
(yrs)
(yrs) T1-hypointense, left
Seizure-fr T2/FLAIR-hyperint
17
21
Seizures
tempor
5.9
ee, no
ense, al lobe
recurrence non-enhancement T1-hypointense,
right
Seizure-fr T2/FLAIR-hyperint
9
13
Seizures
frontal
5.8
ee, no
ense, lobe
recurrence non-enhancement T1-hypointense,
right T2/FLAIR-hyperint 9
14
Seizures
parieta
NA
NA
ense, l lobe non-enhancement T1-hyporintense, right
Seizure-fr T2/FLAIR-hyperint
22.5
23
Seizures
frontal
4.2
ee, no
ense, lobe
recurrence non-enhancement T1-hypointense,
left
Seizure-fr T2/FLAIR-hyperint
7
23
Seizures
tempor
4
ee, no
ense, al lobe
recurrence non-enhancement
left 20
23
T1-hypointense,
Seizures
Seizure-fr 3.3
parieta
T2/FLAIR-hyperint
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ee, no
Accepted Article 7
F
8 M
9
M
l lobe
ense,
recurrence
non-enhancement T1-hypointense, right
Seizure-fr T2/FLAIR-hyperint
5.5
6
Seizures
parieta
2.5
ee, no
ense, l lobe
recurrence non-enhancement T1-hypointense,
right
Seizure-fr T2/FLAIR-hyperint
24
30
Seizures
frontal
0.2
ee, no
ense, lobe
recurrence non-enhancement T1-hypointense,
right
Seizure-fr T2/FLAIR-hyperint
4.7
5
Seizures
frontal
0.1
ee, no
ense, lobe
recurrence non-enhancement
NA= not available
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Table 2 Immunohistochemical findings of the present nine cases
IDH1
GFAP
Vimentin
EMA
D2-40
NeuN
CD34
Ki-67 R132H
Case
BRAF V600E -
+
+
+
+
-
-
Angiocentric glioma: A report of nine new cases, including four with atypical histological features
1
Hai-Chun Ni, MD1,2, Shi-Yun Chen, MD1, Li Chen, MD1, De-Hong Lu, MD1, Yong-Juan Fu, MD1, Yue-Shan Piao, MD1
1
Department of Neuropathology, Xuanwu Hospital, Capital Medical University, Beijing, China 2 Department of Pathology, Central Hospital of Wuhan, Wuhan, China Current address for correspondence and reprint requests: Yue-Shan Piao, MD, Department of Neuropathology, Xuanwu Hospital, Capital Medical University, Chang Chun Street 45, Xicheng District, Beijing 100053, China. E-mail: [email protected] Tel.: +86-10-83198757 We have no conflict of interest. A short running title: Angiocentric glioma with atypical histological features
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/nan.12158 This article is protected by copyright. All rights reserved.
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Abstract Aims: Angiocentric glioma (AG) is a rare, slow-growing tumor of the central nervous system. It is often associated with refractory epilepsy and occurs most commonly in children and young adults. We herein report 9 cases of AG, including 4 with atypical histological findings. Methods: The clinical data and clinicopathological findings of 9 cases with AG histological features were described. Results: All 9 patients had a history of refractory epilepsy with a mean history of 4.4 years and a median age of 17.6 years at surgery. The AG lesions were located in the superficial cerebrocortical region. Histological examination of these cases revealed characteristic structural features of AG, including bipolar spindle-shaped cells with an angiocentric growth pattern. However, 4 cases also exhibited atypical histological features: 1 had astroblastoma-like characteristics, 2 had a distinct cystic region with an onion-like structure and myxoid changes, and the other one had a region involving many abnormal neurons reminiscent to ganglioglioma. All were positive for glial fibrillary acidic protein and vimentin. Eight cases were positive for epithelial membrane antigen (EMA), with a dot-like staining pattern. A diffuse D2-40 staining was visible in these cases, with 2 having similar staining pattern to EMA. All cases were immuno-negative for BRAF V600E and isocitrate dehydrogenase-1 R132H mutations. Conclusions: Our results demonstrate that atypical histological features can be present in AG. A collection of more cases and further molecular analyses are required to confirm our findings. Key words: Angiocentric glioma; Histology; Immunohistochemistry; EMA; D2-40
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INTRODUCTION
Angiocentric glioma (AG) is a rare type of low-grade tumor occurring mainly in
children and young adults (1). It was first reported in 2005 by Lellouch et al. (2) and
Wang et al. (3) and categorized as a distinct clinicopathological entity in the 2007 World Health Organization (WHO) Classification of Tumors of the Central Nervous System (4), where it is described as a “neuroepithelial tumor of uncertain origin,” similar to astroblastoma and chordoid glioma of the third ventricle. AG is often located in the supratentorial region and associated with intractable
epilepsy. Most AG cases exhibit similar magnetic resonance imaging (MRI) features, such as hyperintensity on T2-weighted (T2WI) and fluid-attenuated inversion recovery (FLAIR) images without contrast enhancement after gadolinium administration (2). The histopathological characteristics of AG include a strikingly perivascular growth pattern, monomorphous bipolar cells, and features of ependymal differentiation with dot-like staining for epithelial membrane antigen (EMA) (5). As AG is rare, studies focusing on the disease are limited. To date, approximately
65 AG cases have been reported in the literature. Almost all these cases exhibited characteristic features of AG. We herein report an additional 9 cases of AG with intractable epilepsy. Furthermore, we also reviewed relevant literature and discussed the histological and immunohistochemical features of this relatively new tumor entity.
MATERIALS AND METHODS
Patients
Patients with histological characteristics of AG presented to the Department of
Neuropathology, Xuanwu Hospital, Capital Medical University, from January 2007 to June 2013 were selected. Their clinical data (sex, age at onset and surgery), MRI examinations, and pathological findings were retrospectively reviewed. All included patients were followed up until June 2013. The study was conducted after receiving written informed consent from the patients. In addition, this study was approved by the Institutional Ethics Committee of Xuan Wu Hospital, the Capital Medical University. This article is protected by copyright. All rights reserved.
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Histopathology A standard procedure for processing surgical specimens from patients with
intractable epilepsy was followed (6). For all specimens, coronal sections were
obtained. Selected blocks were processed for embedding in paraffin wax and 4-µm-thick sections were cut and routinely stained with hematoxylin and eosin (H&E). Selected sections were also processed for immunohistochemical studies with the polymer horseradish peroxidase (HRP) detection system (Polink-1 HRP Broad Spectrum DAB Detection Kit; Golden Bridge International, Mukilteo, WA, USA). The following primary antibodies were used: glial fibrillary acidic protein (GFAP; Dako, Glostrup, Denmark; polyclonal, dilution 1:1000), vimentin (Zymed, San Francisco, CA, USA; monoclonal, dilution 1:200), EMA (Zymed; monoclonal, dilution 1:50), podoplanin (Zymed; monoclonal clone D2-40, dilution 1:50), isocitrate dehydrogenase-1 (IDH1) R132H (MBL Company, Japan; monoclonal clone HMab-1, dilution 1:200), CD34 (Zymed; monoclonal, clone QBEnd 10, dilution 1:50), neuronal nuclear antigen (NeuN; Chemicon, Temecula, CA, USA; monoclonal, dilution 1:4000), synaptophysin (Biogenics, San Ramon, CA, USA; monoclonal, dilution 1:50), microtubule-associated protein-2 (MAP-2; Zymed, monoclonal, dilution 1:200), BRAF V600E (Spring Bioscience, Pleasanton, CA, USA; monoclonal clone VE1, dilution 1:50), and Ki-67 (MIB-1; Labvision, Fremont, CA, USA; monoclonal, dilution 1:50).
RESULTS
Patients
From January 2007 to June 2013, we identified 9 patients (5 men and 4 women)
with histological features of AG. Patient clinical data are summarized in Table 1. The patients’ median age at surgery was 17.6 years (range, 5–30 years), and they had a mean history of pre-surgical epilepsy of 4.4 years (range, 0.3–16 years). Among these,
8 cases were available for follow-up. No adjuvant chemotherapy or radiotherapy was administered following surgery. None of the 8 cases experienced seizure attacks or This article is protected by copyright. All rights reserved.
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tumor recurrence in during the follow-up period.
Imaging findings MRI of each patient revealed a well-defined mass in the superficial
cerebrocortical region, including 4 cases in the frontal lobe, 3 in the parietal lobe, and 2 in the temporal lobe. The masses appeared hypointense on T1WI, hyperintense on T2WI and FLAIR, but were non-enhanced after gadolinium contrast injection in all cases (Fig. 1a-f). In cases 6 and 8, the masses had a cystic appearance (Fig. 1g-i).
Histological and immunohistochemical findings Histological examination of the 9 cases revealed typical AG features.
Macroscopically, a tan-gray mass and a blurred cortex-white matter junction were observed in most cases (Fig. 2a). Microscopically, spindle-shaped cells were observed in angiocentric arrangements with circumferential, radial, or longitudinal alignments to both large and small vessels in the cortex and the subcortical white matter in all cases (Fig. 2b-e). The tumor cells appeared monomorphous, bipolar with uniform elongated blind nuclei, minimal cytoplasm, fine stippled chromatin, and inconspicuous nucleoli (Fig. 2f). Elongated cells were also observed orienting perpendicular to the cortical surface, forming a palisade in 6 cases (Fig. 2g). There were also juxtaposed areas of spindle-shaped cells arranged in a fascicular growth pattern, which appeared to be schwannoma-like in 7 cases (Fig. 2h). Entrapped single neurons were often identified within the tumor tissue (Fig. 2i). Adjacent focal cortical dysplasia (FCD) was observed in 6 cases with sufficient tissue for evaluation, and all were classified as FCD IIIb lesions according to the International League against Epilepsy updated category of FCD published in 2011 (7). These lesions with cortical radial and/or tangential abnormalities and cytoarchitectural composition (Fig. 3b-g) were adjacent yet separate from the tumors. No malignant features such as mitotic activity, vascular proliferation, or necrosis were observed in any cases. Microcalcification was observed around the tumor cells only in case 4. The immunohistochemical results are summarized in Table 2. In all 9 cases, tumor This article is protected by copyright. All rights reserved.
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cells were positive for GFAP (Fig. 4a) and vimentin (Fig. 4b), but negative for NeuN, except for neurons in some areas of case 9. Scattered tumor cells exhibited a distinct perinuclear dot-like staining pattern for EMA in 8 cases (Fig. 4c), whereas the other case was EMA-negative. A diffuse D2-40 staining was observed in 9 cases (Fig. 4d), with 2 cases displaying a dot-like staining pattern similar to that of EMA (Fig. 4e). All cases were negative for IDH1 R132H (Fig. 4f) and BRAF V600E. The tumor cells were negative for CD34 with the staining only observable for the blood vessels’ endothelial cells. In all cases, the tumor cells were found to have a low proliferative rate, with a Ki-67 labeling index of 1–5%. In addition to the characteristic AG features, 4 cases also had atypical histological
findings. In case 4, there was a region where unipolar tumor cells with columnar cytoplasm formed a typical astroblastoma-like structure (Fig. 5a-c). These tumor cells with stout processes and distinct cell borders aligned radially along the blood vessels (Fig. 5b-c). They also appeared differently from the spindle-shaped cells in other AG regions of the same case. Although a transitional region with elongated cells arranged in a fascicular and schwannoma-like pattern was present, no other astroblastoma-like feature such as vascular sclerosis or hyalinization was observed. Additionally, Ki-67 results indicated a low labeling index in the astroblastoma-like region. A large cyst with shrinkage of the cortices and gelatinous appearance of the
subcortical white matter was macroscopically visible in case 6 (Fig. 5d). Furthermore, a large cystic pattern and many microcystic formations inside and around the tumor were observable via microscopic examination (Fig. 5e). Typical AG histological features were observed within the cyst, including many bipolar spindle-shaped cells aligned radially or longitudinally along the parenchymal blood vessels (Fig. 5f). Similarly, cystic and microcystic formations were also observed in case 8. However,
part of the tumor contained bipolar, spindle-shaped cells forming an onion-like structure (Fig. 5g, h). Additionally, myxoid changes were noted in the cystic and onion-like structure (Fig. 5i). In case 9, a typical AG structure was observed with many abnormal neurons in the
tumor and adjacent cortex (Fig. 6a, b). These abnormal neurons appeared similar to This article is protected by copyright. All rights reserved.
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the “dysplastic neurons” often observed in a ganglioglioma (GG). They were ganglion-like, with vesicular nuclei and prominent nucleoli. Furthermore, perimembranous aggregated Nissl substance and occasional double-nucleus neurons were also observed. In addition to these morphological features, the neurons were abnormally distributed. The abnormal neurons were often identified within the tumor tissue of the AG lesion (Fig. 6f) with a progressive increase in numbers from the AG center to the transitional region and subsequently, the covering cortex (Fig. 6e–h). They were immunoreactive for the neuronal marker MAP-2 (Fig. 6d) and synaptophysin (Fig. 6e), but negative for CD34 and BRAF V600E.
DISCUSSION
Our cases presented various histological features of AG, astroblastoma-like feature,
distinct large cystic region with an onion-like structure, cystic and microcystic formations, and many abnormal neurons reminiscent to ganglioglioma (GG). A review of 65 reported AG cases (Tab. 3) suggested that the disease predominantly
occurred in children and young adults, with a median age of 16.0 ± 14.3 years (range, 2–70 years) at the time of surgical treatment. The male-to-female ratio was
approximately 1.5:1 (39/26). Clinical features were available for 59 cases, and 52 (88%) of these patients presented with intractable epilepsy. The majority of AG cases have similar MRI features such as hyperintensity on
T2WI and FLAIR as well as no contrast enhancement after gadolinium administration (2). However, T1WI results are less consistent, ranging from hypo- to hyperintense. Several cases showed subtle or mild enhancement after gadolinium administration (8-13). Three patients have shown cystic changes (12, 14, 15) and 2 have shown calcification (5, 16) on MRI. The main histopathological feature of AG is an angiocentric growth pattern of
bipolar spindle cells with ependymal features. In some cases, elongated cells arranged in schwannoma-like nodules or occasional round epithelioid cells in a nest-and-sheet arrangement are also observed (2–5). Besides these common histopathological This article is protected by copyright. All rights reserved.
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features,
other
atypical
findings
have
been
reported
in
AG,
including
calcifications/microcalcifications (7/65 cases, 11%) (2, 9, 12, 17–19) and microcystic/cystic changes (9/65 cases, 14%) (2, 3, 10, 19 ， 20). Furthermore, Buccoliero et al. described tumor cells embedded in a mucoid matrix and some microcalcifications in an AG case (12). Lu et al. reported the case of a 15-year-old boy involving a tumor with 2 distinct appearances, including AG characteristics and glioblastoma-like features (11). Recently, Miyata et al. suggested a rare but distinct clinicopathological subset of AG characterized by adult onset, mesial temporal lobe localization, and epithelioid cell-predominant histology (15). Based on the above-mentioned studies and the 2007 WHO classification, all of the
9 cases in this report fitted with an AG diagnosis. Interestingly, atypical histological findings were also observed in 4 cases, including an astroblastoma-like structure in 1 case, cystic and onion-like structures with myxoid changes in 2 cases, and abnormal neurons in another case. Astroblastoma-like structures are very rare in AG with only 1 case previously reported by Wang et al. (3). Additionally, Bonnin et al. also described perivascular cells with stout processes and distinct cell borders creating perivascular formations of astroblastoma type in some areas (21). Astroblastoma is a rare and controversial glial neoplasm that has not been universally accepted as a distinct entity. Astroblastoma and AG are of uncertain histogenesis and occur more frequently in children and young adults. Both of them present as superficial, cortical-based tumors with a distinct angiocentric growth pattern and GFAP expression. Therefore, to distinguish between AG and astroblastoma is challenging, particularly given the overlap between the 2 tumor types. However, to our knowledge, astroblastoma has never been reported with monomorphous and bipolar spindle-shaped cells as seen in AG. Thus, the tumor in our case was best diagnosed as an AG with an astroblastoma-like structure. In cases 6 and 8, a large cystic pattern and many microcystic formations inside and
around the tumors were observed with the former apparent in both imaging findings and gross examinations. Such a cystic pattern is more commonly observed macroscopically in scar tissue, but very rarely in AG. Of the 65 cases reported in the
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literature, only 3 cases exhibited cystic changes on imaging (12, 14, 15), and 9 cases had microcystic or large cystic patterns identified via histopathological studies (2, 3, 10, 19, 20). Lellouch et al. (2) reported 10 AG cases, including 3 with a microcystic pattern with 1 having a large cystic cavity. Liu et al. (20) also reported microcystic formation within the tumor in their case. Hu et al. (10) speculated that the cystic pattern in their case might be attributed to previous tumor hemorrhage. However, tumor hemorrhages were not observed in our cases. In case 8, besides the cystic pattern, part of the tumor region contained bipolar,
spindle-shaped cells arranged in an onion-like manner with myxoid changes observable in the cystic and onion-like structures. Such an onion-like structure with myxoid changes has not been reported in AG. The pattern of bipolar, spindle-shaped cells orienting towards the vessels and myxoid changes within the lesion resemble features of pilomyxoid astrocytoma (PMA) (22). However, the tumor cells were immunoreactive for EMA in this case, whereas EMA staining is often absent in PMA. Moreover, the cystic pattern was observable in imaging studies, gross examinations, and histopathological analysis, especially in the case with an onion-like structure and myxoid changes. Such observations have not been reported previously in the literature. A typical AG structure mixed with abnormal neurons was observed in case 9. GG,
the most common low-grade glioneuronal tumor, is often associated with refractory epilepsy (23). Except for the neoplastic glial element, the most significant feature of GG is the ganglion-like neurons, which was difficult to distinguish from the abnormal neurons in our case. However, other evidences of GG such as Rosenthal fibers or lymphocytes infiltration were not detectable in this case. Although some GG cases are negative for CD34, the stem cell marker is reportedly helpful for the disease identification (24). Additionally, BRAF V600E mutation can be detected in
approximately 50% of all GG cases (25). However, the abnormal neurons in our case, which we preferably defined as “entrapped neurons”, were negative for both CD34 and BRAF V600E. Furthermore, many infiltrative gliomas are diagnosed as GG because the differences between entrapped distorting and dysplastic neurons are This article is protected by copyright. All rights reserved.
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difficult to identify (25, 26). Indeed, many authors have considered the nerve cells interspersed within the tumor tissue in AG, which lacks neoplastic or dysplastic features, as preexisting neurons of the cerebral cortex diffusely infiltrated by the tumor (3, 5, 8, 9, 18). However, the neurons in this case presented in much greater abundance than previously reported, exhibiting some dysplastic features. Therefore, a collection of more cases and further molecular analyses are warranted to confirm whether such abnormal neurons resulted from an acquired dysplasia secondary to the principle lesion development (7). Similar to previously reported results, the tumor cells in these 9 AG cases were
immunoreactive for GFAP and vimentin, but negative for NeuN and IDH1 R132H. Ependymomatous features are frequently associated with a dot-like microlumen-type cytoplasmic staining for EMA. Of 52 cases available in the literature, dot-like cytoplasmic immunoreactivity for EMA was found in 48 cases (2, 3, 5, 9, 11-16, 20, 27-33). The other 4 cases were negative for EMA (8, 10, 18). However, the functional role of EMA expression in AG remains to be elucidated. We particularly believe that most AG cases might have ependymomatous features owing to the common expression of EMA in AG. The expression of D2-40 was also observed in our AG cases. D2-40 is a
monoclonal antibody originally raised against an unidentified protein derived from germ-cell tumors (34). D2-40 is considered a useful diagnostic marker for ependymal tumors, especially in combination with EMA (35). Preusser et al. (5) reported D2-40 expression in 8 AG cases. We also observed diffuse immunoreactivity for D2-40 in all of our cases, with 2 exhibiting a dot-like pattern similar to that of EMA staining. In accordance with a benign clinical behavior, AG characteristically exhibits a low
proliferative rate, with Ki-67 labeling indexes ranging from 1% to 5%. Most reports and WHO studies have indicated that AG is a slow-growing tumor with a low proliferative rate. The Ki-67 labeling indexes were lower than 5% in all of our cases. However, 7 AG cases have been previously reported with a high Ki-67 labeling index or malignant features (3, 11, 13, 15, 18, 26,28). In order to further explore the molecular pathogenesis and signature of AG, the
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expression of IDH1 R132H and BRAF V600E was assessed in our cases. Point
mutations of the IDHl gene have been described in almost 40% of grade II diffuse
gliomas but are not observable in grade I gliomas such as PA and GG (26). Activating mutations of BRAF are present at a high frequency in PA and GG yet less commonly in malignant gliomas. Thus, a combined analysis of IDH1 and BRAF can improve diagnostic accuracy in distinguishing grade I and malignant gliomas (25). A recent study utilizing high-resolution comparative genomic hybridization (CGH) points to genetically distinct subsets of diffuse low-grade gliomas suggested that tumors with complex chromosomal aberrations were often more aggressive (37). Moreover, another recent study involving patients with low-grade diffuse gliomas reported a
longer survival in those with 1p/19q +/- IDH1/2 mutations than those who with TP53 +/- IDH1/2 mutations (38). CGH has previously revealed a focal chromosomal loss involving 6q24-q25 as the only alteration in 1 of 8 cases with a high-resolution screen by array-CGH identifying a copy number gain at 11p11.2 containing the protein-tyrosine phosphatase receptor-type gene in 1 of 3 cases (25). In the few AG cases evaluated, loss of 1p/19q has not been shown (25). Among the 65 cases reported in the literature, only 3 series with 7 cases mentioned IDH1 and/or BRAF mutations in AG (11, 12, 31). In agreement with the above-mentioned reports, the expression of IHD1 R132H and BRAF V600E was not detected in any of our cases. To further study the molecular pathogenesis and signature of AG, a collection of more cases and further molecular analyses are definitely required.
CONCLUSIONS
We herein reported 9 cases with almost typical clinical, radiological, and
histological features of AG. Four cases also exhibited atypical histological features. One case had an astroblastoma-like feature; 2 had a distinct cystic region, with 1 having an onion-like structure and myxoid changes, and the remaining case presented with many abnormal neurons reminiscent to those in GG. Additional cases are required to confirm and extend the understanding of AG. Since the disease is rare, we
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believe that each new case should be carefully examined to clarify the biological behavior of this newly defined neoplasm.
Acknowledgments The author thanks Prof. Komori Takashi for his helpful opinion, and thanks Yang Hong, Zhao Li-hong and Wei Li-feng for their technical assistance. This work was supported by grants to Yue-Shan Piao from the Beijing Municipal Health Bureau “215 project”(No. 2011-3-095).
Author contributions. Collected clinical and imaging dada: H-C Ni and S-Y Chen. Analyzed the immunohistochemistry results: L Chen, D-H Lu, Y-J Fu and Y-S Piao. Contributed analysis diagnostic results and discussion: H-C Ni, S-Y Chen, L Chen, D-H Lu and Y-S Piao.Wrote the paper: H-C Ni, S-Y Chen and Y-S Piao.
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Table 1 Main clinical findings of the present nine cases
Cas
Se
e
x
1
2
3
4
5
6
M
M
F
F
M
F
Epilep sy
Surge
Clinical
Followlocatio
onset
ry age
presentati
MRI
up
Outcome
n age
(yrs)
on
(yrs)
(yrs) T1-hypointense, left
Seizure-fr T2/FLAIR-hyperint
17
21
Seizures
tempor
5.9
ee, no
ense, al lobe
recurrence non-enhancement T1-hypointense,
right
Seizure-fr T2/FLAIR-hyperint
9
13
Seizures
frontal
5.8
ee, no
ense, lobe
recurrence non-enhancement T1-hypointense,
right T2/FLAIR-hyperint 9
14
Seizures
parieta
NA
NA
ense, l lobe non-enhancement T1-hyporintense, right
Seizure-fr T2/FLAIR-hyperint
22.5
23
Seizures
frontal
4.2
ee, no
ense, lobe
recurrence non-enhancement T1-hypointense,
left
Seizure-fr T2/FLAIR-hyperint
7
23
Seizures
tempor
4
ee, no
ense, al lobe
recurrence non-enhancement
left 20
23
T1-hypointense,
Seizures
Seizure-fr 3.3
parieta
T2/FLAIR-hyperint
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ee, no
Accepted Article 7
F
8 M
9
M
l lobe
ense,
recurrence
non-enhancement T1-hypointense, right
Seizure-fr T2/FLAIR-hyperint
5.5
6
Seizures
parieta
2.5
ee, no
ense, l lobe
recurrence non-enhancement T1-hypointense,
right
Seizure-fr T2/FLAIR-hyperint
24
30
Seizures
frontal
0.2
ee, no
ense, lobe
recurrence non-enhancement T1-hypointense,
right
Seizure-fr T2/FLAIR-hyperint
4.7
5
Seizures
frontal
0.1
ee, no
ense, lobe
recurrence non-enhancement
NA= not available
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Accepted Article
Table 2 Immunohistochemical findings of the present nine cases
IDH1
GFAP
Vimentin
EMA
D2-40
NeuN
CD34
Ki-67 R132H
Case
BRAF V600E -
+
+
+
+
-
-
