November 2022 – Neuropathology and Surgical Pathology

A 34-year-old right-handed woman with a history of intractable epilepsy underwent a right frontal craniotomy for resection of a brain lesion.

She experienced her first seizure episode at age 23. Her seizures consisted of a fidgeting movement, speech interruption and feeling of anxiety, as well as occasional left head turn, or pacing in circles while she is standing. Interictal EEG displayed potential epileptogenic activity in the bifrontal regions (R>L), as well as infrequent right temporal activity. A brain MRI, as shown below, revealed a mildly abnormal contour in the anterior paramedian right frontal gyrus, with underlying T2 hyperintensity in the subcortical white matter, with no apparent mass effect. 

Figure 1
Figure 2
Figure 3

The micrographs above show a representative section from the lesion, including immunostains for crystallin, GFAP, IDH, and NeuN. What is incorrect about this patient’s underlying neurological condition?

  1. This lesion is characterized by cortical dyslamination, and dysmorphic neurons with balloon cells.
  2. This lesion is caused by alterations of TSC1/TSC2 genes.
  3. Activation of mTOR pathway and phosphorylation of tau plays a role in pathogenesis.
  4. Hemimegalencephaly should be in differential diagnosis.

The correct answer is ...

This lesion is caused by alterations of TSC1/TSC2 genes.

The correct diagnosis is focal cortical dysplasia, ILAE type IIb. H&E on representative sections shows portions of cerebral cortex and subcortical white matter with multifocal collections of balloon cells, which are alpha-beta crystallin immunoreactive. NeuN demonstrates focal disorganization of the laminar neuronal architecture of the background cerebral cortex, with a focal collection of dysmorphic neurons. GFAP highlights subpial and subcortical reactive gliosis. No evidence of an atypical infiltrating glial cell population is identified; IDH1 R132H immunohistochemistry is negative in tissue. These findings support the diagnosis. 

Focal cortical dysplasia (FCD) is a malformation of cortical development, which can lead to interactable focal epilepsy.2 Characterized by specific cytological and architectural abnormalities, it usually involves a small portion of one gyrus (that may be enlarged).4 Histologically, cortical lamination and organization is disrupted (choice A). In the most recent classification by the International League Against Epilepsy (ILAE) there are three main types each with several subtypes introduced with revisions to the criteria.5

FCD types I and III are characterized by dyslamination and disrupted organization of tissue architecture, but with morphologically normal neurons and glial cells.5 FCD II is distinguished from FCD I and III by dysplastic, megalocytic neurons admixed with normal neurons. Subtype IIb is further characterized by the presence of balloon cells, which express both neuronal and glial protein transcription products; hence, are considered to be from a mixed lineage.2

Balloon cells can also be present in hemimegalencephaly (HME) (choice D) and tuberous sclerosis. In fact, microscopically, FCD II and HME are identical, with both showing similar dyslaminated cortex, abnormal glial cells, dysplastic neurons, and balloon cells mixed with normal glia and neurons.5 The main difference between FCD IIb and HME is the extent of the lesion. Being derived from an earlier developmental stage, HME tends to involve much larger areas up to a lobe or even entire hemisphere.6 Similar histopathological findings can be seen in the cortical tubers of tuberous sclerosis, however, it is distinguished from FCD and HME with dystrophic calcifications, and absence of the characteristic alterations of TSC1 (tuberin) and TSC2 (hamartin) (choice B).1 However, the pathogenesis of these three disorders similarly involves the activation of mammalian target of rapamycin (mTOR) signalling pathway3 and phosphorylation of tau; hence known collectively as infantile tauopathies (choice C).8


  1. Jozwiak J. Hamartin and tuberin: working together for tumour suppression. Int J Cancer. 2006 Jan 1;118(1):1-5. doi:10.1002/ijc.21542. PMID: 16206276
  2. Lamparello P, Baybis M, Pollard J, Hol EM, Eisenstat DD, Aronica E, Crino PB. Developmental lineage of cell types in cortical dysplasia with balloon cells. Brain. 2007 Sep;130(Pt 9):2267-76. doi:10.1093/brain/awm175. PMID: 17711980
  3. Lim JS, Kim WI, Kang HC, Kim SH, Park AH, Park EK, Cho YW, Kim S, Kim HM, Kim JA, Kim J, Rhee H, Kang SG, Kim HD, Kim D, Kim DS, Lee JH. Brain somatic mutations in MTOR cause focal cortical dysplasia type II leading to intractable epilepsy. Nat Med. 2015 Apr;21(4):395-400. doi:10.1038/nm.3824. Epub 2015 Mar 23. PMID: 25799227
  4. Miyata H, Hori T, Vinters HV. Surgical pathology of epilepsy-associated non-neoplastic cerebral lesions: a brief introduction with special reference to hippocampal sclerosis and focal cortical dysplasia. Neuropathology. 2013 Aug;33(4):442-58. doi:10.1111/neup.12028. Epub 2013 Mar 27. PMID: 23530853; PMCID: PMC4120885.
  5. Najm IM, Sarnat HB, Blümcke I. Review: The international consensus classification of Focal Cortical Dysplasia - a critical update 2018. Neuropathol Appl Neurobiol. 2018 Feb;44(1):18-31. doi:10.1111/nan.12462. PMID: 29359399.
  6. Severino M, Geraldo AF, Utz N, Tortora D, Pogledic I, Klonowski W, Triulzi F, Arrigoni F, Mankad K, Leventer RJ, Mancini GMS, Barkovich JA, Lequin MH, Rossi A. Definitions and classification of malformations of cortical development: practical guidelines. Brain. 2020 Oct 1;143(10):2874-2894. doi: 10.1093/brain/awaa174. Erratum in: Brain. 2020 Dec 1;143(12): e108. PMID: 32779696; PMCID: PMC7586092.
  7. Siedlecka M, Grajkowska W, Galus R, Dembowska-Bagińska B, Jóźwiak J. Focal cortical dysplasia: Molecular disturbances and clinicopathological classification (Review). Int J Mol Med. 2016 Nov;38(5):1327-1337. doi:10.3892/ijmm.2016.2760. Epub 2016 Sep 29. PMID: 28025990
  8. Sarnat HB, Flores-Sarnat L. Infantile tauopathies: Hemimegalencephaly; tuberous sclerosis complex; focal cortical dysplasia 2; ganglioglioma. Brain Dev. 2015 Jun;37(6):553-62. doi:10.1016/j.braindev.2014.08.010. Epub 2014 Oct 19. PMID: 25451314.

Amir Nazem, M.D., Ph.D.

Resident, Anatomic/Neuropathology 
Mayo Clinic

Jorge Lopez-Trejo, M.D.

Senior Associate Consultant, Anatomic Pathology
Mayo Clinic
Assistant Professor of Laboratory Medicine and Pathology
Mayo Clinic College of Medicine and Science

MCL Education

This post was developed by our Education and Technical Publications Team.