Toward a better definition of focal cortical dysplasia: An iterative histopathological and genetic agreement trial

Abstract

Objective 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. Methods 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. Results 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. Significance 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.

Integrated genotype–phenotype analysis of long‐term epilepsy‐associated ganglioglioma

“…Panel‐based targeted sequencing is widely used nowadays for routine molecular diagnostics, but limited data are available about the diagnostic yield and sensitivity when using epilepsy surgery samples with abnormal cells admixed with preexisting normal neuroepithelial cells ( 46 ). The lack of identifiable genetic alterations in our cohort may also be due to the limitation of the chosen gene panel.…”

DNA methylation-based classification of malformations of cortical development in the human brain

“…Next, we tested both models against an independent test cohort ( n = 43), including 18 samples obtained from the most recent ILAE FCD agreement trial [ 9 ]. These difficult-to-classify surgical brain samples obtained from pediatric and adult focal epilepsy patients had undergone multiple rounds of histopathological evaluations by 13 international expert neuropathologists to achieve an agreement on the diagnosis and were now analyzed for DNA methylation.…”

“…All cases included into this study have been extensively studied at the microscopic level with Hematoyxlin–Eosin and Cresyl Violet – Luxol Fast Blue stainings available from all FFPE surgical tissue blocks. An immunohistochemistry panel of antibodies recommended for the neuropathology work-up of epilepsy surgery specimens [ 7 , 9 ], including NeuN, MAP2, GFAP, Vimentin, neurofilament SMI32, Ki67, OLIG2, CD34, CD68 and CD45 epitopes were also made available for each case. Each diagnosis was finally agreed upon consensus by two of our coauthors (IB and RC) applying the International League Against Epilepsy (ILAE) classification system of 2011 [ 13 ] and 2013 [ 12 ].…”

“…The test cohort included 43 independent retrospective surgical samples, including a series of 18 patients provided through the epilepsy surgery program of the Cleveland Clinic, USA. These cases underwent independent iterative evaluation by 20 neuropathologists from 15 different countries and were previously published in the ILAE FCD agreement trial of histopathology and genetic testing [ 9 ]. Another 25 samples were provided through the European Epilepsy Brain Bank (EEBB).…”

Histopathological Correlations of Qualitative and Quantitative Temporopolar MRI Analyses in Patients With Hippocampal Sclerosis

“…Such a finding has been observed in patients with long-term epilepsy and reported under a wide range of descriptive terms, such as glioneuronal hamartia (30), microdysgenesis (8,9,31), oligodendroglial hyperplasia (10,15), and oligodendrogliosis (32,33). Recently, an entity was proposed in patients with early-onset frontal lobe epilepsy and designated as mild developmental cortical malformation with oligodendroglial hyperplasia (34,35). This myriad of terms has been used for patients with temporal (8,9,30,36,37) or frontal lobe epilepsy (15,34) and associated with different pathological conditions (32).…”