Department of Neuropathology, University Hospital, Erlangen, Germany.
Epilepsy Center, Cleveland Clinic, Cleveland, OH, USA.
Epilepsia. 2021 Jun;62(6):1416-1428. doi: 10.1111/epi.16899. Epub 2021 May 5.
Focal cortical dysplasia (FCD) is a major cause of difficult-to-treat epilepsy in children and young adults, and the diagnosis is currently based on microscopic review of surgical brain tissue using the International League Against Epilepsy classification scheme of 2011. We developed an iterative histopathological agreement trial with genetic testing to identify areas of diagnostic challenges in this widely used classification scheme.
Four web-based digital pathology trials were completed by 20 neuropathologists from 15 countries using a consecutive series of 196 surgical tissue blocks obtained from 22 epilepsy patients at a single center. Five independent genetic laboratories performed screening or validation sequencing of FCD-relevant genes in paired brain and blood samples from the same 22 epilepsy patients.
Histopathology agreement based solely on hematoxylin and eosin stainings was low in Round 1, and gradually increased by adding a panel of immunostainings in Round 2 and the Delphi consensus method in Round 3. Interobserver agreement was good in Round 4 (kappa = .65), when the results of genetic tests were disclosed, namely, MTOR, AKT3, and SLC35A2 brain somatic mutations in five cases and germline mutations in DEPDC5 and NPRL3 in two cases.
The diagnoses of FCD 1 and 3 subtypes remained most challenging and were often difficult to differentiate from a normal homotypic or heterotypic cortical architecture. Immunohistochemistry was helpful, however, to confirm the diagnosis of FCD or no lesion. We observed a genotype-phenotype association for brain somatic mutations in SLC35A2 in two cases with mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy. Our results suggest that the current FCD classification should recognize a panel of immunohistochemical stainings for a better histopathological workup and definition of FCD subtypes. We also propose adding the level of genetic findings to obtain a comprehensive, reliable, and integrative genotype-phenotype diagnosis in the near future.
局灶性皮质发育不良（FCD）是儿童和年轻成人中难以治疗的癫痫的主要原因，目前的诊断基于使用 2011 年国际抗癫痫联盟分类方案对手术脑组织进行微观检查。我们开发了一种具有遗传测试的迭代组织病理学一致性试验，以确定该广泛使用的分类方案中的诊断挑战领域。
来自 15 个国家的 20 名神经病理学家完成了 4 项基于网络的数字病理学试验，使用来自单个中心的 22 名癫痫患者的连续系列 196 个手术组织块。来自同一 22 名癫痫患者的脑组织和血液样本的 5 个独立基因实验室对 FCD 相关基因进行了筛选或验证测序。
仅基于苏木精和伊红染色的组织病理学一致性在第 1 轮较低，并且在第 2 轮添加免疫组化面板和第 3 轮 Delphi 共识方法后逐渐增加。当公布遗传测试结果时，即 5 例中存在 MTOR、AKT3 和 SLC35A2 脑体细胞突变，2 例中存在 DEPDC5 和 NPRL3 种系突变时，第 4 轮的观察者间一致性良好（kappa =.65）。
FCD 1 型和 3 型亚型的诊断仍然最具挑战性，通常难以将其与正常同型或异型皮质结构区分开来。然而，免疫组织化学有助于确认 FCD 或无病变的诊断。我们观察到 2 例伴有轻度皮质发育不良畸形和癫痫的少突胶质细胞增生的 SLC35A2 脑体细胞突变的基因型-表型相关性。我们的结果表明，目前的 FCD 分类应认识到一组免疫组织化学染色，以进行更好的组织病理学检查和 FCD 亚型的定义。我们还建议在不久的将来添加遗传发现的水平，以获得全面、可靠和综合的基因型-表型诊断。
