According to the WHO classification, ependymal tumors are classified as subependymomas, myxopapillary ependymomas, classic ependymomas, anaplastic ependymomas, and RELA-fusion-positive ependymomas (RELA-EPN). Among classic ependymomas, the WHO defines rare histological variants, i.e., the clear cell, papillary, and tanycytic ependymoma. In parallel, global DNA methylation patterns distinguish nine molecular groups, some of which tightly overlap with histopathological subgroups. However, the match of the aforementioned histological variants to DNA methylation classes remains unclear. We analyzed histomorphology, clinical parameters, and global DNA methylation of tumors with the initial histological diagnoses of tanycytic (n = 12), clear cell (n = 14), or papillary ependymoma (n = 19). Forty percent of these tumors did not match to the epigenetic profile of ependymomas, using a previously published DNA methylation-based classifier for brain tumors. Instead, they were classified as low-grade glioma (n = 3), plexus tumor (n = 2), CNS high-grade neuroepithelial tumor with MN1 alteration (n = 2), papillary tumor of the pineal region (n = 2), neurocytoma (n = 1), or did not match to any known brain tumor methylation class (n = 8). Overall, integrated diagnosis had to be changed in 35.6% of cases as compared to the initial diagnosis. Among the tumors molecularly classified as ependymoma (27/45 cases), tanycytic ependymomas were mostly located in the spine (5/7 cases) and matched to spinal or myxopapillary ependymoma. 6/8 clear cell ependymomas were found supratentorially and fell into the methylation class of RELA-EPN. Papillary ependymomas with a positive ependymoma match (12/19 cases) showed either a "papillary" (n = 5), a "trabecular" (n = 1), or a "pseudo-papillary" (n = 6) growth pattern. The papillary growth pattern was strongly associated with the methylation class B of posterior fossa ependymoma (PFB, 5/5 cases) and tumors displayed DNA methylation sites that were significantly different when compared to PFB ependymomas without papillary growth. Tumors with pseudo-papillary histology matched to the methylation class of myxopapillary ependymoma (4/6 cases), whereas the trabecular case was anatomically and molecularly a spinal ependymoma. Our results show that the diagnosis of histological ependymoma variants is challenging and epigenetic profiles may improve diagnostic accuracy of these cases. Whereas clear cell and papillary ependymomas display correlations between localization, histology, and methylation, tanycytic ependymoma does not represent a molecularly distinct subgroup.

中文翻译：

---

组织病理学室管膜瘤变体的分子表征。

根据WHO的分类，室间隔瘤分为室管膜下瘤，粘膜乳头管膜瘤，经典室管膜瘤，间变性室管膜瘤和RELA融合阳性室管膜瘤（RELA-EPN）。在经典的室间隔膜瘤中，WHO定义了罕见的组织学变异，即透明细胞，乳头状和单核细胞室间隔膜瘤。同时，总体DNA甲基化模式可区分9个分子组，其中一些与组织病理学亚组紧密重叠。然而，上述组织学变体与DNA甲基化类别的匹配仍不清楚。我们分析了组织形态学，临床参数和肿瘤的整体DNA甲基化，并初步对单核细胞增多症（n = 12），透明细胞（n = 14）或乳头状室间隔瘤（n = 19）进行了组织学诊断。使用先前发表的基于DNA甲基化的脑肿瘤分类器，这些肿瘤中有40％与室管膜瘤的表观遗传特征不匹配。相反，它们被分类为低度神经胶质瘤（n = 3），丛神经瘤（n = 2），具有MN1改变的CNS高度神经上皮肿瘤（n = 2），松果体区域的乳头状肿瘤（n = 2） ，神经细胞瘤（n = 1）或与任何已知的脑肿瘤甲基化类别（n = 8）不匹配。总体而言，与初始诊断相比，在35.6％的病例中必须更改综合诊断。在分子分类为室间隔膜瘤的肿瘤（27/45例）中，单核细胞性室间隔膜瘤多数位于脊柱（5/7例），并与脊柱或粘膜乳头状室间隔瘤相匹配。在幕上发现6/8个透明细胞室间隔膜瘤，属于RELA-EPN的甲基化类别。室间隔膜瘤匹配阳性的乳头室间隔膜瘤（12/19例）显示出“乳头状”（n = 5），“小梁”（n = 1）或“假性乳头状”（n = 6）生长模式。乳头状增生模式与后颅窝室间隔瘤的甲基化B级密切相关（PFB，5/5例），并且肿瘤显示的DNA甲基化位点与无乳头状增长的PFB室间隔瘤相比有显着差异。具有假乳头组织学的肿瘤与粘液性乳头膜室膜瘤的甲基化类别相匹配（4/6例），而小梁的病例在解剖学和分子上是脊柱室管膜瘤。我们的结果表明，组织学性室管膜瘤变型的诊断具有挑战性，表观遗传学特征可能会提高这些病例的诊断准确性。