Autopsy findings of previously described case of diffuse intrinsic pontine glioma-like tumor with EZHIP expression and molecular features of PFA ependymoma,Acta Neuropathologica Communications

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Autopsy findings of previously described case of diffuse intrinsic pontine glioma-like tumor with EZHIP expression and molecular features of PFA ependymoma
Acta Neuropathologica Communications ( IF 6.2 ) Pub Date : 2021-06-23 , DOI: 10.1186/s40478-021-01215-5
Murad Alturkustani _{1,

2} , Jennifer A Cotter _{1,

3} , Roshan Mahabir ₁ , Debra Hawes _{1,

3} , Carl Koschmann _{4,

5} , Sriram Venneti _{5,

6} , Alexander R Judkins _{1,

3} , Linda J Szymanski _{1,

3}

Affiliation

We wanted to expand on the pathological findings of the recently published case report of a diffuse intrinsic pontine glioma (DIPG)-like tumor with EZHIP expression and methylation features of childhood posterior fossa group A (PFA) ependymoma by Pratt et al. [5] by describing the postmortem brain examination findings. The previous case report described an unusual brainstem glioma with characteristic radiographic and histopathologic features of DIPG (based on biopsy), but with methylation features of PFA ependymoma. The 5-year-old male patient underwent multiple rounds of radiation, but died 18 months later. At the family’s request, a postmortem examination was performed to better characterize this tumor.

Postmortem examination of the brain confirmed that the brainstem was expanded by a large lobulated tan-gray tumor that distorted the cranial nerves and encased the basilar artery (Fig. 1a, b). There was opacification of the leptomeninges near the mammillary bodies corresponding to leptomeningeal spread (Fig. 1c). Axial sections through the brainstem revealed the tumor was partially solid and infiltrative, centered in the pons and extended into the midbrain and cerebellum. Solid tumor nodules were noted near the fourth ventricle.

Histopathological examination of the pons demonstrated a tumor with two distinct growth patterns consisting of either solid nodules of hypercellular tumor or diffusely infiltrative tumor. Neoplastic cells in both components demonstrated eosinophilic cytoplasm, and oval nuclei with a salt-and-pepper chromatin pattern. In the solid component within the pons, ependymal rosettes, perivascular pseudorosettes (Fig. 1d, e) and focal areas of astroblastic rosettes occasionally surrounding hyalinized blood vessels suggestive of ependymal differentiation were encountered. Minimal necrotic changes were noted that were likely secondary to treatment related effects. There was no significant endothelial proliferation or mitotic activity.

The infiltrative component extended beyond the pons and involved the midbrain, bilateral thalami (Fig. 1f), left basal ganglia and temporal lobe superiorly; the medulla inferiorly, and the cerebellar white matter, cortex and dentate nuclei (Fig. 1g) dorsally as well as the basal leptomeninges and leptomeninges of the mamillary bodies. Throughout, tumor cells formed Scherer’s secondary structures around neurons and blood vessels, under the pia and along white matter tracts. There were rare mitoses. The tumor cells were viable and there were no significant treatment related effects. The immunohistochemical findings were similar in both components. Immunohistochemistry showed tumor immunoreactivity for GFAP, EMA (strong and diffuse dot-like positivity) (Fig. 1h), and EZHIP (Fig. 1j). There was loss of nuclear expression of H3K27me3 (Fig. 1i).

Local infiltration can be seen in low-grade glial neoplasms including ependymomas. However, an infiltrative growth pattern is typically considered diagnostic of a diffuse glioma and is not the expected behavior in an ependymoma. Distal infiltration is a criterion used by the recent cIMPACT-NOW guidelines to distinguish diffuse midline glioma from other well-circumscribed gliomas with H3K27 mutation [4]. This tumor demonstrates a fairly unique histology with a prominent infiltrative pattern of growth which we have not previously encountered nor is well described in ependymomas.

This case illustrates the challenges in incorporating the morphologic and molecular features of some pediatric tumors into a single integrated diagnosis based on the current WHO classification of tumors of the central nervous system [3]. The histology within the solid components and immunohistochemical profile of GFAP positivity and EMA perinuclear dot-like positivity is consistent with a classic ependymoma without high-grade features. Olig2 was not interpretable in the autopsy specimen as internal positive control was negative, but Olig2 was reported as negative in the preceding biopsy sample. While this lack of expression is more consistent with ependymal differentiation, it is not 100% specific as a subset of astrocytomas lack Olig2 expression as well [2]. The absence of nuclear expression of H3K27me3 and expression of EZHIP by immunohistochemical staining further helps in subclassification of the tumor as a PFA ependymoma. At the same time, the histology within the infiltrative pattern of growth with rare mitoses is consistent with a diffuse glioma without high-grade features (brisk mitotic count, microvascular proliferation or necrosis). In that context, the same pattern of H3K27me3 and EZHIP expression has been recently described in a subclass of diffuse midline glioma and would therefore establish a different diagnosis [1]. Consequently, this tumor poses a challenge for neuropathologists as the diagnosis rendered may vary based both on where the tumor was biopsied (solid vs infiltrative nodules) and their interpretation of the current WHO classification and cIMPACT-NOW guidelines.

In summary, this unusual brain tumor arising within the pons clinically met the criteria for a DIPG but upon biopsy examination demonstrated H3K27me3 global reduction, EZHIP overexpression and methylation profile that cluster with group ‘EPN, PFA’ despite a lack of apparent ependymal histologic features [5]. Subsequent postmortem examination revealed both well-developed ependymal features and extensive infiltrative growth and leptomeningeal spread, not detected clinically or radiologically. This difference highlights the importance of autopsy examination in characterizing tumor histology and growth pattern to better understand the full range of features of these complex diseases. This case also illustrates the difficulties that may be encountered in harmonizing the distinct molecular and histopathological features of some pediatric CNS tumors within the current WHO classification and cIMPACT-NOW guidelines. This will perhaps be aided by further study and characterization of the infiltrative component of this lesion, but also perhaps by the continued development of pediatric specific CNS entities within the WHO classification and cIMPACT-NOW guidelines.

1.
Castel D, Kergrohen T, Tauziede-Espariat A, Mackay A, Ghermaoui S, Lechapt E, Pfister SM, Kramm CM, Boddaert N, Blauwblomme T, Puget S, Beccaria K, Jones C, Jones DTW, Varlet P, Grill J, Debily MA (2020) Histone H3 wild-type DIPG/DMG overexpressing EZHIP extend the spectrum diffuse midline gliomas with PRC2 inhibition beyond H3–K27M mutation. Acta Neuropathol 139:1109–1113. https://doi.org/10.1007/s00401-020-02142-w
Article PubMed Google Scholar
2.
Joseph NM, Phillips J, Dahiya S, Felicella M, Tihan T, Brat DJ, Perry A (2013) Diagnostic implications of IDH1-R132H and OLIG2 expression patterns in rare and challenging glioblastoma variants. Mod Pathol 26:315–326. https://doi.org/10.1038/modpathol.2012.173
CAS Article PubMed Google Scholar
3.
Louis DN, Ohgaki H, Wiestler OD, Cavenee WK (2016) WHO classification of tumours of the central nervous system. Intl. Agency for Research, City.
4.
Louis DN, Giannini C, Capper D, Paulus W, Figarella-Branger D, Lopes MB, Batchelor TT, Cairncross JG, van den Bent M, Wick W, Wesseling P (2018) cIMPACT-NOW update 2: diagnostic clarifications for diffuse midline glioma, H3 K27M-mutant and diffuse astrocytoma/anaplastic astrocytoma, IDH-mutant. Acta Neuropathol 135:639–642. https://doi.org/10.1007/s00401-018-1826-y
Article PubMed Google Scholar
5.
Pratt D, Quezado M, Abdullaev Z, Hawes D, Yang F, Garton HJL, Judkins AR, Mody R, Chinnaiyan A, Aldape K, Koschmann C, Venneti S (2020) Diffuse intrinsic pontine glioma-like tumor with EZHIP expression and molecular features of PFA ependymoma. Acta Neuropathol Commun 8:37-w. https://doi.org/10.1186/s40478-020-00905-w
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We thank Fusheng Yang who performed immunohistochemistry.

The authors declare that they have no funding.

Affiliations

Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
Jennifer A. Cotter, Debra Hawes, Alexander R. Judkins & Linda J. Szymanski
Department of Pathology and Laboratory Medicine, Children’s Hospital of Los Angeles, Los Angeles, CA, USA
Murad Alturkustani, Jennifer A. Cotter, Roshan Mahabir, Debra Hawes, Alexander R. Judkins & Linda J. Szymanski
Department of Pathology, University of Michigan School of Medicine, Ann Arbor, MI, USA
Sriram Venneti
Division of Pediatric Hematology/Oncology, Department of Pediatrics, C.S. Mott Children’s Hospital, University of Michigan, 1500 E Medical Center Dr, Ann Arbor, MI, 48109, USA
Carl Koschmann
Laboratory of Brain Tumor Metabolism and Epigenetics, Department of Pathology, University of Michigan, 3520E MSRB 1, 1150 W. Medical Center, Ann Arbor, MI, 48109, USA
Carl Koschmann & Sriram Venneti
King Abdulaziz University, Jeddah, Saudi Arabia
Murad Alturkustani

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Debra HawesView author publications
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Carl KoschmannView author publications
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Sriram VennetiView author publications
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Alexander R. JudkinsView author publications
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Linda J. SzymanskiView author publications
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Contributions

MA and LS wrote the manuscript and designed the figures. MA, RM, and LS performed the autopsy and histologic review. DH and ARJ interpreted IHC. JC and SV supervised the project. CK supervised the project and provided clinical care. The authors read and approved the final manuscript.

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Correspondence to Murad Alturkustani.

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Alturkustani, M., Cotter, J.A., Mahabir, R. et al. Autopsy findings of previously described case of diffuse intrinsic pontine glioma-like tumor with EZHIP expression and molecular features of PFA ependymoma. acta neuropathol commun 9, 113 (2021). https://doi.org/10.1186/s40478-021-01215-5

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Received: 16 April 2021
Accepted: 08 June 2021
Published: 23 June 2021
DOI: https://doi.org/10.1186/s40478-021-01215-5

中文翻译：

先前描述的具有 EZHIP 表达和 PFA 室管膜瘤分子特征的弥漫性内在脑桥胶质瘤样肿瘤病例的尸检结果

我们希望扩展 Pratt 等人最近发表的具有 EZHIP 表达和儿童后颅窝 A 组 (PFA) 室管膜瘤甲基化特征的弥漫性内在脑桥胶质瘤 (DIPG) 样肿瘤病例报告的病理结果。[5] 通过描述死后脑部检查结果。先前的病例报告描述了一种不寻常的脑干胶质瘤，具有 DIPG 的特征性放射学和组织病理学特征（基于活检），但具有 PFA 室管膜瘤的甲基化特征。这名 5 岁男性患者接受了多轮放疗，但在 18 个月后死亡。应家人的要求，进行了尸检以更好地表征这种肿瘤。

大脑的尸检证实，脑干被一个大的分叶状棕褐色肿瘤扩张，扭曲了颅神经并包裹了基底动脉（图 1a，b）。与软脑膜扩散相对应的乳头体附近存在软脑膜混浊（图 1c）。通过脑干的轴向切片显示肿瘤部分实性和浸润性，以脑桥为中心并延伸至中脑和小脑。在第四脑室附近发现实体瘤结节。

脑桥的组织病理学检查显示肿瘤具有两种不同的生长模式，包括多细胞肿瘤的实性结节或弥漫性浸润性肿瘤。两种成分中的肿瘤细胞均表现出嗜酸性的细胞质和具有椒盐染色质模式的椭圆形核。在脑桥内的固体成分中，遇到室管膜玫瑰花结、血管周围的假玫瑰花结（图 1d、e）和星形胶质玫瑰花结的局灶区域，偶尔会出现在提示室管膜分化的透明血管周围。注意到可能继发于治疗相关效应的最小坏死变化。没有显着的内皮增殖或有丝分裂活性。

浸润成分超出脑桥并累及中脑、双侧丘脑（图 1f）、左侧基底节和颞叶；髓质下方，小脑白质，皮质和齿状核（图1g），以及乳头体的基底软脑膜和软脑膜。在整个过程中，肿瘤细胞在神经元和血管周围、软脑膜下方和白质束周围形成了 Scherer 的二级结构。有罕见的有丝分裂。肿瘤细胞是活的并且没有显着的治疗相关效果。两种成分的免疫组化结果相似。免疫组织化学显示 GFAP、EMA（强和弥漫性点样阳性）（图 1h）和 EZHIP（图 1j）的肿瘤免疫反应性。H3K27me3的核表达缺失（图1i）。

在包括室管膜瘤在内的低级别胶质瘤中可见局部浸润。然而，浸润性生长模式通常被认为是弥漫性神经胶质瘤的诊断，而不是室管膜瘤的预期行为。远端浸润是最近 cIMPACT-NOW 指南用于区分弥漫性中线胶质瘤与其他具有 H3K27 突变的界限清楚的胶质瘤的标准 [4]。这种肿瘤表现出相当独特的组织学，具有显着的浸润性生长模式，我们以前没有遇到过这种情况，也没有在室管膜瘤中得到很好的描述。

该病例说明了将一些儿科肿瘤的形态学和分子特征纳入基于当前 WHO 中枢神经系统肿瘤分类的单一综合诊断中的挑战 [3]。GFAP 阳性和 EMA 核周点样阳性的实体成分内的组织学和免疫组化特征与没有高级特征的经典室管膜瘤一致。Olig2 在尸检样本中无法解释，因为内部阳性对照为阴性，但 Olig2 在之前的活检样本中报告为阴性。虽然这种缺乏表达与室管膜分化更一致，但它并不是 100% 特异性的，因为星形细胞瘤的一个子集也缺乏 Olig2 表达 [2]。通过免疫组织化学染色，H3K27me3 的核表达和 EZHIP 的表达缺失进一步有助于将肿瘤亚分类为 PFA 室管膜瘤。同时，具有罕见有丝分裂的浸润性生长模式内的组织学与没有高级特征（快速有丝分裂计数、微血管增殖或坏死）的弥漫性胶质瘤一致。在这种情况下，H3K27me3 和 EZHIP 表达的相同模式最近在弥漫性中线胶质瘤的一个亚类中得到了描述，因此将建立不同的诊断 [1]。因此，这种肿瘤对神经病理学家提出了挑战，因为根据肿瘤活检的位置（实性结节与浸润性结节）以及他们对当前 WHO 分类和 cIMPACT-NOW 指南的解释，做出的诊断可能会有所不同。

总之，这种在脑桥内出现的不寻常的脑肿瘤临床上符合 DIPG 的标准，但活检检查显示 H3K27me3 整体减少、EZHIP 过表达和甲基化谱与“EPN、PFA”组聚集，尽管缺乏明显的室管膜组织学特征[ 5]。随后的尸检显示室管膜发育良好，广泛浸润性生长和软脑膜扩散，临床或放射学均未检测到。这种差异凸显了尸检在表征肿瘤组织学和生长模式以更好地了解这些复杂疾病的全部特征方面的重要性。该案例还说明了在当前 WHO 分类和 cIMPACT-NOW 指南中协调某些儿科 CNS 肿瘤的独特分子和组织病理学特征时可能遇到的困难。这可能会通过进一步研究和表征这种病变的浸润成分得到帮助，但也可能通过在 WHO 分类和 cIMPACT-NOW 指南中继续发展儿科特定的 CNS 实体。

1.
Castel D, Kergrohen T, Tauziede-Espariat A, Mackay A, Ghermaoui S, Lechapt E, Pfister SM, Kramm CM, Boddaert N, Blauwblomme T, Puget S, Beccaria K, Jones C, Jones DTW, Varlet P, Grill J, Debily MA (2020) 过表达 EZHIP 的组蛋白 H3 野生型 DIPG/DMG 将 PRCR2 抑制作用扩展到 H3–K27M 突变之外的谱弥漫性中线神经胶质瘤。神经病理学杂志一百三十九：1109—1113。https://doi.org/10.1007/s00401-020-02142-w
文章 PubMed 谷歌学术
2.
Joseph NM, Phillips J, Dahiya S, Felicella M, Tihan T, Brat DJ, Perry A (2013) IDH1-R132H 和 OLIG2 表达模式在罕见和具有挑战性的胶质母细胞瘤变体中的诊断意义。Mod Pathol 26：315—326。https://doi.org/10.1038/modpathol.2012.173
CAS 文章 PubMed 谷歌学术
3.
Louis DN, Ohgaki H, Wiestler OD, Cavenee WK (2016) WHO 中枢神经系统肿瘤分类。国际机场市研究机构。
4.
Louis DN, Giannini C, Capper D, Paulus W, Figarella-Branger D, Lopes MB, Batchelor TT, Cairncross JG, van den Bent M, Wick W, Wesseling P (2018) cIMPACT-NOW 更新 2：弥漫性中线的诊断说明胶质瘤，H3 K27M 突变体和弥漫性星形细胞瘤/间变性星形细胞瘤，IDH 突变体。神经病理学杂志一百三十五：639—642。https://doi.org/10.1007/s00401-018-1826-y
文章 PubMed 谷歌学术
5.
Pratt D, Quezado M, Abdullaev Z, Hawes D, Yang F, Garton HJL, Judkins AR, Mody R, Chinnaiyan A, Aldape K, Koschmann C, Venneti S (2020) 弥漫性固有脑桥胶质瘤样肿瘤与 EZHIP 表达和分子PFA室管膜瘤的特点。Acta Neuropathol Commun 8:37-w。https://doi.org/10.1186/s40478-020-00905-w
文章谷歌学术

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隶属关系

南加州大学凯克医学院，美国加利福尼亚州洛杉矶
Jennifer A. Cotter、Debra Hawes、Alexander R. Judkins 和 Linda J. Szymanski
病理学和检验医学部，洛杉矶儿童医院，洛杉矶，加利福尼亚州，美国
Murad Alturkustani、Jennifer A. Cotter、Roshan Mahabir、Debra Hawes、Alexander R. Judkins 和 Linda J. Szymanski
密歇根大学医学院病理学系，美国密歇根州安娜堡
斯里拉姆文内蒂
密歇根大学 CS Mott 儿童医院儿科儿科血液/肿瘤科，1500 E Medical Center Dr, Ann Arbor, MI, 48109, USA
卡尔·科施曼
密歇根大学病理学系脑肿瘤代谢和表观遗传学实验室, 3520E MSRB 1, 1150 W. Medical Center, Ann Arbor, MI, 48109, USA
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MA 和 LS 撰写了手稿并设计了图形。MA、RM 和 LS 进行了尸检和组织学检查。DH 和 ARJ 解释了 IHC。JC 和 SV 监督了该项目。CK监督该项目并提供临床护理。作者阅读并批准了最终手稿。

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Alturkustani, M., Cotter, JA, Mahabir, R.等。先前描述的具有 EZHIP 表达和 PFA 室管膜瘤分子特征的弥漫性内在脑桥胶质瘤样肿瘤病例的尸检结果。神经病理学学报 9, 113 (2021)。https://doi.org/10.1186/s40478-021-01215-5

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