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Coexistent ganglioglioma, focal cortical dysplasia, and hippocampal sclerosis (triple pathology) in chronic epilepsy
Annals of Diagnostic Pathology xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Annals of Diagnostic Pathology
Original Contributions
Coexistent ganglioglioma, focal cortical dysplasia, and hippocampal sclerosis (triple pathology) in chronic epilepsy Richard A. Prayson, MD, MEd ⁎, Jordan M. Gales, BS Cleveland Clinic Department of Anatomic Pathology and Cleveland Clinic Lerner College of Medicine, Cleveland, OH
a r t i c l e
i n f o
Available online xxxx Keywords: Hippocampal sclerosis Epilepsy Ganglioglioma Focal cortical dysplasia Triple pathology
a b s t r a c t The most commonly identified pathologies in patients with medically intractable epilepsy include focal cortical dysplasia, hippocampal sclerosis, tumors, and remote ischemic damage. Surgery has proven to be an effective therapeutic modality in most of such patients. The coexistence of multiple pathologies in resected tissues is well documented, particularly ganglioglioma and focal cortical dysplasia. Cases of triple pathology are, however, extraordinarily unusual. We report 2 cases of triple pathology including hippocampal sclerosis, ganglioglioma, and focal cortical dysplasia. Cases of pathologically confirmed hippocampal sclerosis diagnosed between January 2000 to December 2012 (n= 349) were reviewed, and only 2 cases (0.6%) with triple pathology were identified. The histopathologic and clinical features of these 2 cases are reviewed. The patients included a 6-year-old girl and 10-year-old boy. The former patient presented with a 4-year history of epilepsy and oppositional defiant disorder. Imaging identified a lesion in the left parahippocampal gyrus and posterior hippocampus. The latter patient presented with an 8-year history of epilepsy, attention deficient hyperactivity disease, and a pervasive developmental disorder. Imaging identified a lesion in the left posterior temporal and occipital region. Resected tissues in both patients showed a ganglioglioma (World Health Organization grade I) with accompanying focal cortical dysplasia and hippocampal sclerosis. Both patients were seizure free on antiepileptic medication at last follow-up at 20 and 38 months, respectively. The prevalence of triple pathology including hippocampal sclerosis is low (b1% in the current study). Surgical intervention for triple pathology cases anecdotally appears effective in achieving seizure control. © 2015 Elsevier Inc. All rights reserved.
1. Introduction
2. Methods and materials
The pathologic substrates underlying pharmacoresistent epilepsy have been well described and most commonly involve hippocampal sclerosis (in patients with temporal lobe epilepsy), focal cortical dysplasia, remote infarcts/contusional damage, and neoplasms [1-5]. In most patients who undergo surgical resection, an imaging abnormality or pathologic abnormality is identified grossly or upon microscopic examination, although there are a small percentage of cases in which no obvious pathologic or imaging findings are noted (so-called nonlesional cases) [6]. Occasionally, more than 1 pathology, which independently can be causative of epilepsy, may be identified in resected tissues, so-called dual pathology. These most commonly involve combinations of tumor and focal cortical dysplasia or hippocampal sclerosis and focal cortical dysplasia [7-11]. Only rare instances of triple pathology, where 3 potentially etiologic lesions coexist in the same patient, have been reported [12-15]. This article reports 2 cases of triple pathology in pediatric patients with a history of medical intractable epilepsy who underwent surgical resection of the epileptogenic focus.
Institutional review board approval was obtained before commencement of the study. The anatomic pathology files were searched for cases of hippocampal sclerosis diagnosed between January 2000 and December 2012. All such cases were reviewed to confirm a diagnosis of hippocampal sclerosis, using criteria outlined by the International League against Epilepsy (ILAE) group [16]. Three hundred forty-nine cases were identified. Of those cases, 2 patients had coexistent ganglioglioma and focal cortical dysplasia excised at the same time. Criteria for the diagnosis of ganglioglioma outlined by the World Health Organization (WHO) were used in classifying the tumors [17]. Classification of the focal cortical dysplasia patterns observed used the Palmini et al. [18] and more recent ILAE approaches [7]. Medical records were reviewed for pertinent clinical information. Ki-67 immunostaining (prediluted; Ventana, Tucson, AZ) was performed in each tumor; 1000 tumor cells from the area of the tumor with the most staining were assessed, and a labeling index was determined (ie, percentage of positive staining tumor cells). 3. Results 3.1. Patient 1
⁎ Corresponding author at: Department of Anatomic Pathology, L25, Cleveland Clinic, 9500 Euclid Ave, Cleveland, OH, 44195, USA. Tel.: +1 216 444 8805; fax: +1 216 445 6967. E-mail address: [email protected] (R.A. Prayson).
The patient was a 6-year-old, left-handed girl who presented at age 2 years with new-onset seizures. There was no history of birth or head
http://dx.doi.org/10.1016/j.anndiagpath.2015.07.003 1092-9134/© 2015 Elsevier Inc. All rights reserved.
Please cite this article as: Prayson RA, Gales JM, Coexistent ganglioglioma, focal cortical dysplasia, and hippocampal sclerosis (triple pathology) in chronic epilepsy, Ann Diagn Pathol (2015), http://dx.doi.org/10.1016/j.anndiagpath.2015.07.003
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R.A. Prayson, J.M. Gales / Annals of Diagnostic Pathology xxx (2015) xxx–xxx
trauma, infection, or infantile febrile seizures. Her seizures were of 2 types: tonic seizures and seizures marked by staring episodes and unresponsiveness. Seizures were localized by electroencephalogram studies to the left anterior mesial and basal temporal lobe. The patient was also diagnosed with oppositional defiant disorder. Initially, the seizures responded to antiepileptic medication (Tegretol). The physical examination was normal. Magnetic resonance imaging (MRI) studies showed abnormal signal on T2-weighted-Fluid-Attenuated Inversion Recovery images in the left parahippocampal gyrus and posterior hippocampus with a small cystic area and indistinct gray-white junction. No enhancement was noted. The possibility of a low-grade glioma with associated focal cortical dysplasia was raised. The patient underwent left temporal lobectomy with resection of mesial structures. Histologic sections from the hippocampus (totally submitted) showed loss of neurons and gliosis predominantly involving the CA1 and CA4 regions of the hippocampus, consistent with classic hippocampal sclerosis (ILAE type Ia) (Fig. 1A). A section from the totally submitted amygdala showed occasional collections of small round neurons (hamartia). Sections from the subtotally sampled left temporal lobe was marked by a focal area of increased cellularity composed of a proliferation of atypical astrocytic cells with an intermixed neuronal cell component, consistent with a ganglioglioma, WHO grade I (Fig. 1B). Dystrophic calcifications are present in the tumor. Mitotic activity, vascular proliferative changes, and necrosis were not seen. A Ki-67 labeling index of 0.6% was observed. The adjacent temporal lobe parenchyma was marked by mild focal cortical architectural organization, principally in a horizontal orientation, consistent with focal cortical dysplasia (Palmini et al. type IA, resembling an ILAE type Ib pattern) (Fig. 1C). Balloon cells, dysmorphic neurons, and neuronal cytomegaly were not observed in areas of focal cortical dysplasia. Focally, Chaslin gliosis (subpial gliosis) was observed. At the last known follow-up 20 months postoperatively, the patient was seizure free on antiepileptic medication. 3.2. Patient 2 The patient was a 9-year-old, left-handed man who presented with a new-onset, grand mal seizure at age 9 months. Seizures typically consisted of arrested activity with staring and deviation of the head and eyes to the right. Seizures were adequately controlled with medications for the first 2 years. There was no history of birth or head trauma, infection, or infantile febrile seizures. Electroencephalogram localized the seizures to the left temporal and occipital lobe regions. He was also diagnosed with attention deficit hyperactivity syndrome with a pervasive developmental disorder. An MRI done after the first seizure showed subtle enlargement of the posterior temporal-occipital region. Repeat MRI studies 5 years later showed increased T2/FLAIR signal in the posterior medial left temporal lobe, which was interpreted as most likely representing focal cortical dysplasia. A positron emission tomography scan showed severe hypometabolism in the left medial and posterior temporal lobe and left inferior and medial occipital lobe cortex. Histologic sections from the left hippocampus, which was totally submitted for pathologic examination, showed severe loss of neurons accompanied by gliosis in the CA1 and CA4 regions (severe hippocampal sclerosis, ILAE type Ib) (Fig. 2A). The left amygdala was totally submitted for pathologic examination and showed nonspecific gliosis and perivascular white matter atrophy. Sections from the subtotally submitted temporal and occipital lobe resection showed a focally microcystic neoplasm characterized by a proliferation of atypical appearing astrocytic cells intermixed with an atypical neuronal cell component (Fig. 2B). Foci of perivascular chronic inflammation, consisting primarily of benign appearing lymphocytes, and microcalcifications were observed in the tumor. Mitotic activity, vascular proliferative changes, and necrosis were not observed. The morphology of the tumor was consistent with that of a ganglioglioma, WHO grade I. A Ki-67 labeling
Fig. 1. Patient 1. Left hippocampus showing a prominent loss of neurons and gliosis in the CA1 or Sommer sector region (lower right) and a relative sparing of neurons in the CA2 region (top) (hematoxylin and eosin, original magnification × 50) (A). Patient 1. An abnormal clustering of ganglionic cells arranged against a hypercellular background resembling a low-grade astrocytoma in a ganglioglioma situated in the left temporal lobe (hematoxylin and eosin, original magnification ×200) (B). Patient 1. Superficial temporal lobe cortex adjacent to the tumor showing an absence of cortical layer 2, consistent with focal cortical dysplasia and subpial gliosis (hematoxylin and eosin, original magnification ×100) (C).
index of 0.9% was focally observed (Fig. 2C). The adjacent temporal and occipital lobe cortex showed focal architectural disorganization in both a horizontal and vertical orientation, consistent with a Palmini et al. type IA focal cortical dysplasia, resembling an ILAE type Ic pattern (Figs. 2D and E). Dysmorphic neurons, neuronal cytomegaly, and balloon cells were not noted in areas of focal cortical dysplasia. In addition, focal areas of Chaslin gliosis were observed. At last known follow-up 38 months after surgery, the patient was seizure free on antiepileptic medication.
Please cite this article as: Prayson RA, Gales JM, Coexistent ganglioglioma, focal cortical dysplasia, and hippocampal sclerosis (triple pathology) in chronic epilepsy, Ann Diagn Pathol (2015), http://dx.doi.org/10.1016/j.anndiagpath.2015.07.003
R.A. Prayson, J.M. Gales / Annals of Diagnostic Pathology xxx (2015) xxx–xxx
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Fig. 2. Patient 2. Left hippocampus showing a marked loss of neurons within the CA4 or endplate region (hematoxylin and eosin, original magnification ×100) (A). Patient 2. Left temporal lobe mass marked by focal microscystic change and a proliferation of atypical-appearing neuronal cells admixed with an atypical astrocytic cell proliferation (hematoxylin and eosin, original magnification ×100) (B). Patient 2. Ki-67 immunostain showing only rare positive staining tumor cell nuclei (original magnification ×200) (C). Patient 2. An area of focal cortical dysplasia near the ganglioglioma marked by a loss of cortical layer 2 and a malpositioning of neuronal cells (hematoxylin and eosin, original magnification ×200) (D). Patient 2. Another area adjacent to the tumor showing focal cortical dysplasia with columnar arrangements of neurons in the cortex (hematoxylin and eosin, original magnification ×200) (E).
4. Discussion The association of certain low-grade neoplasms with focal cortical dysplasia is well established. Certain glioneuronal neoplasms, which are common in the chronic epilepsy setting, notably gangliogliomas and dysembryoplastic neuroepithelial tumors, have been both well described as being frequently associated with adjacent focal cortical dysplasia [19-22]. Less commonly, reports of other less frequently encountered neoplasms in this setting, such as pleomorphic xanthoastrocytoma and angiocentric glioma, have been anecdotally described as sometimes being associated with focal cortical dysplasia [23,24]. The tumor-like meningioangiomatosis, which frequently presents with epilepsy, has
also recently been acknowledged to be sometimes associated as well [25]. In most of these cases, the histologic pattern of dysplasia often falls into the type I category [8]. The recent ILAE consensus classification for focal cortical dysplasia formally acknowledges these associations and designates these lesions as type IIIb [7]. The exact nature of these relationships is currently not completely understood, and a number of hypotheses have been suggested. The frequency of the coexistence, particularly with dysembryoplastic neuropepithelial tumors and in some series with gangliogliomas, suggests some sort of relationship. Perhaps the coexistent lesions represent different phenotypic appearances of a common disruption in development. Perhaps they represent opposite ends of a spectrum (diffuse vs
Please cite this article as: Prayson RA, Gales JM, Coexistent ganglioglioma, focal cortical dysplasia, and hippocampal sclerosis (triple pathology) in chronic epilepsy, Ann Diagn Pathol (2015), http://dx.doi.org/10.1016/j.anndiagpath.2015.07.003
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focal lesion). Perhaps one lesion gives rise to the other in certain circumstances or under certain genetic or environmental conditions. The clinical significance lies in the implication for surgical management and seizure outcomes. In most of the tumors, the neoplasm itself is electrically silent, and seizures are emanating from adjacent tissue [26]. Excision of the tumor alone likely leaves behind adjacent areas of focal cortical dysplasia, which may contribute to continued seizures or the development of recurrent seizures. The association of hippocampal sclerosis with focal cortical dysplasia is also well established [7]. The reported prevalence of this coexistence is variable and has ranged from rare to relatively common. No obvious etiology or clinicopathologic phenotype is associated with these cases, which is a source of continue conjecture in this area as to the precise nature of the coexistence [27]. The ILAE classification of focal cortical dysplasia formally recognized this association and denotes these cases as representing type IIIa dysplasia [7]. Whether the changes seen in this setting are acquired, that is, the hippocampal sclerosis lesion and focal cortical dysplasia result from reorganization (dysplasia) or injury resulting in hippocampal sclerosis, or these cases represent a distinct developmental abnormality whereby the hippocampal sclerosis develops secondary to chronic epilepsy resulting from the focal cortical dysplasia lesion is uncertain. The lack of clinical differences and postsurgical outcomes between hippocampal sclerosis and hippocampal sclerosis with focal cortical dysplasia patients would argue for a common etiology [28,29]. Only anecdotal prior case reports of triple pathology have been reported [30,13,12]. In 2009, Samura et al. reported a case of cavernoma associated with focal cortical dysplasia and hippocampal sclerosis presenting in a 33-year-old woman who had seizures since age 2 years arising in the right frontotemporal region. The focal cortical dysplasia was marked by the presence of dysmorphic neurons and an absence of balloon cells. The patient was seizure free 12 months after surgery on antiepileptic medication. Maciunas et al [30] reported a similar case of cavernoma associated with focal cortical dysplasia and hippocampal sclerosis in a 63-year-old man who had seizures staring at age 25 years culminating in a resection of the left anterior temporal lobe, amygdala, and hippocampus. The dysplasia resembled a Palmini et al. type IB pattern. The patient had been seizure free 18 months after surgery; it is unclear whether the patient was still on antiseizure medication. Cheong et al. [13] reported a case of a 27-year-old man who was diagnosed with seizures at age 16 years and who developed remote ischemic changes; Rasmussen encephalitis; and type II dysplasia, not further delineated, in the right frontotemporal lobe region. The patient was reported to be seizure free after surgery, but no interval of time was reported, or whether the patient was still taking antiepileptic medications. The only case of triple pathology involving a tumor was reported by Yang et al [12] in 2013. They presented a case of a 29-year-old man who presented with recurrent seizures for a 4-year period and who underwent resection of the right anterior temporal lobe, hippocampus, and amygdala. Histologic examination of resected tissues revealed a ganglioglioma, WHO grade I, focal cortical dysplasia (type IIA), and hippocampal sclerosis. The patient had been seizure free on antiepileptic medications for the 8 months after surgery. The 2 cases reported in the current series were similar in that they also involved the temporal lobe. The coexistent dysplasia patterns were ILAE type I/Palmini et al. type I lesions, phenotypically similar to most cases of dysplasia seen with low-grade glioneuronal tumors and hippocampal sclerosis. Both of the current cases have been seizure free on antiepileptic medications for 20 and 38 months, suggesting that good seizure outcome, at least in the short term, may be attainable in these cases, despite the presence of triple pathology. Long-term prognosis may be dependent on the extent of the focal cortical dysplasia in these patients, whether dysplasia tissue
was left behind and if something may happen in the future to trigger seizure activity in any residual dysplasia tissue. References [1] Prayson RA. Diagnostic challenges in the evaluation of chronic epilepsy-related surgical neuropathology. Am J Surg Pathol 2010;34:e1-13. [2] Pasquier B, Bost F, Peoc’h M, Barnoud R, Pasquier D. Neuropathological findings in resective surgery for medically intractable epilepsy: a study of 195 cases. Ann Pathol (Paris) 1996;16:174–81. [3] Wolf HK, Muller MB, Spanle M, Zentner J, Schramm J, Wiestler OD. Surgical pathology of chronic epileptic seizure disorders. Brain Pathol 1993;35:1130–5. [4] Bourgeois M, Sainte-Rose C, Lellouch-Tubiana A, Malucci C, Brunelle F, Maixner W, et al. Surgery of epilepsy associated with focal lesions in childhood. J Neurosurg 1999;90:833–42. [5] Plate KH, Wieser HG, Yasargil MG, Wiestler OD. Neuropathological findings in 224 patients with temporal lobe epilepsy. Acta Neuropathol 1993;86:433–8. [6] Wang ZI, Alexopoulos AV, Jones SE, Jaisani Z, Najm IM, Prayson RA. The pathology of magnetic resonance imaging negative epilepsy. Mod Pathol 2013;26:1051–8. [7] Blumcke I, Thom M, Aronica E, Armstrong D, Vinters HV, Palmini A. The clinicopathologic spectrum of focal cortical dysplasias: a consensus classification proposed by an ad hoc Task Force of the ILAE Diagnostic Methods Commission. Epilepsia 2011;52:158–74. [8] Prayson RA, Fong J, Najm I. Coexistent pathology in chronic epilepsy patients with neoplasms. Mod Pathol 2010;23:1097–103. [9] Cendes F, Cook MJ, Watson C, Andermann F, Fish DR, Shorvon SD. Frequency and characteristics of dual pathology in patients with lesional epilepsy. Neurology 1995;45:2058–64. [10] Li LM, Cendes F, Andermann F, Watson C, Fish DR, Cook MJ. Surgical outcome in patients with epilepsy and dual pathology. Brain 1999;122:799–805. [11] Fauser S, Schulze-Bonhage A, Honegger J, Carmona H, Huppertz HJ, Pantazis G. Focal cortical dysplasias: surgical outcome in 67 patients in relation to histological subtypes and dual pathology. Brain 2004;127:2406–18. [12] Yang K, Su J, Hu Z, Lang R, Sun X, Li X. Triple pathology in patients with temporal lobe epilepsy: a case report and review of the literature. Exp Ther Med 2013;6:925–8. [13] Cheong JY, Wong C, Bleasel A, Varikatt W, Ng T, Dexter MA. Late onset Rasmussen's encephalitis with triple pathology. J Clin Neurosci 2009;16:1677–81. [14] Maciunas JA, Syed TU, Cohen ML, Werz MA, Maciunas RJ, Koubeissi MZ. Triple pathology in epilepsy: coexistence of cavernous angiomas and cortical dysplasia with other lesions. Epilepsy Res 2010;91:106–10. [15] Samura K, Morioka T, Hashiguchi K, Miyagi Y, Shigeto H, Sakata A, et al. Temporal lobe epilepsy associated with ‘triple pathology’ of hippocampal sclerosis, focal cortical dysplasia and cavernoma in the ipsilateral frontal lobe. Epilepsy Seizure 2009;2:34–41. [16] Blumcke I, Thom M, Aronica E, Armstrong DD, Bartolomei F, Bernasconi A. International consensus classification of hippocampal sclerosis in temporal lobe epilepsy: a Task Force report from the ILAE Commission on Diagnostic Methods. Epilepsia 2013;54:1315–29. [17] Becker A, Wiestler O, Figarella-Branger D, Blumcke I. Ganglioglioma and Gangliocytoma. WHO classification of tumours of the central nervous system. Lyon, FR: IARC Press; 2007. p. 103–5. [18] Palmini A, Najm I, Avanzini G, Babb T, Guerrini R, Foldvary-Schaefer N. Terminology and classification of the cortical dysplasias. Neurology 2004;62:S2–8. [19] Prayson RA, Khajavi K, Comair YG. Cortical architectural abnormalities and MIB-1 immunoreactivity in gangliogliomas: a study of 60 patients with intracranial tumors. J Neuropathol Exp Neurol 1994;54:513–20. [20] Wolf HK, Muller MB, Spanle M, Zentner J, Schramm J, Wiestler OD. Ganglioglioma: a detailed histopathological and immunohistochemical analysis of 61 cases. Acta Neuropathol 1994;88:166–73. [21] Dysembryoplastic neuroepithelial tumor: a surgically curable tumour of young patients with intractable partial seizures. Neurosurgery 1988;23:545–56. [22] Daumas-Duport C, Scheithauer BW, Chodkiewicz JP, Laws Jr ER, Vedrenne C. Dysembryoplastic neuroepithelial tumours. Brain Pathol 1993;3:283–95. [23] Lach B, Duggal N, DaSilva VF, Benoit BG. Association of pleomorphic xanthoastrocytoma with cortical dysplasia and neuronal tumors: a report of three cases. Cancer 1996;78:2551–63. [24] Marburger T, Prayson R. Angiocentric glioma: a clinicopathologic review of 5 tumors with identification of associated cortical dysplasia. Arch Pathol Lab Med 2011;135: 1037–41. [25] Grabowski MM, Prayson RA. Focal cortical dysplasia in meningioangiomatosis. Clin Neuropathol 2015;34:76–82. [26] Fischer-Williams M, Dike GL. Brain tumors and other space-occupying lesions. In: Niedermeyer E, DaSilva FL, editors. Electroencephalography: basic principles, clinical applications, and related fields. 3rd ed. Baltimore, MD: Williams and Wilkins; 1993. p. 305–432. [27] Spreafico R, Blumcke I. Focal cortical dysplasias: clinical implication of neuropathological classification systems. Acta Neuropathol 2010;120:359–67. [28] Tassi L, Garbelli R, Columbo N, et al. Type I focal cortical dysplasia: surgical outcome is related to histopathology. Epileptic Disord 2010;12:181–91. [29] Thom M, Eriksson S, Martinian L, Caboclo LO, McEvoy AW, Duncan JS. Temporal lobe sclerosis associated with hippocampal sclerosis in temporal lobe epilepsy: neuropathological features. J Neuropathol Exp Neurol 2009;68:928–38. [30] Maciunas JA, Syed TU, Cohen ML, Werz MA, Maciunas RJ, Koubeissi MZ. Triple pathology in epilepsy: coexistence of cavernous angiomas and cortical dysplasias with other lesions. Epilepsy Res 2010;91:106–10.
Please cite this article as: Prayson RA, Gales JM, Coexistent ganglioglioma, focal cortical dysplasia, and hippocampal sclerosis (triple pathology) in chronic epilepsy, Ann Diagn Pathol (2015), http://dx.doi.org/10.1016/j.anndiagpath.2015.07.003
Contents lists available at ScienceDirect
Annals of Diagnostic Pathology
Original Contributions
Coexistent ganglioglioma, focal cortical dysplasia, and hippocampal sclerosis (triple pathology) in chronic epilepsy Richard A. Prayson, MD, MEd ⁎, Jordan M. Gales, BS Cleveland Clinic Department of Anatomic Pathology and Cleveland Clinic Lerner College of Medicine, Cleveland, OH
a r t i c l e
i n f o
Available online xxxx Keywords: Hippocampal sclerosis Epilepsy Ganglioglioma Focal cortical dysplasia Triple pathology
a b s t r a c t The most commonly identified pathologies in patients with medically intractable epilepsy include focal cortical dysplasia, hippocampal sclerosis, tumors, and remote ischemic damage. Surgery has proven to be an effective therapeutic modality in most of such patients. The coexistence of multiple pathologies in resected tissues is well documented, particularly ganglioglioma and focal cortical dysplasia. Cases of triple pathology are, however, extraordinarily unusual. We report 2 cases of triple pathology including hippocampal sclerosis, ganglioglioma, and focal cortical dysplasia. Cases of pathologically confirmed hippocampal sclerosis diagnosed between January 2000 to December 2012 (n= 349) were reviewed, and only 2 cases (0.6%) with triple pathology were identified. The histopathologic and clinical features of these 2 cases are reviewed. The patients included a 6-year-old girl and 10-year-old boy. The former patient presented with a 4-year history of epilepsy and oppositional defiant disorder. Imaging identified a lesion in the left parahippocampal gyrus and posterior hippocampus. The latter patient presented with an 8-year history of epilepsy, attention deficient hyperactivity disease, and a pervasive developmental disorder. Imaging identified a lesion in the left posterior temporal and occipital region. Resected tissues in both patients showed a ganglioglioma (World Health Organization grade I) with accompanying focal cortical dysplasia and hippocampal sclerosis. Both patients were seizure free on antiepileptic medication at last follow-up at 20 and 38 months, respectively. The prevalence of triple pathology including hippocampal sclerosis is low (b1% in the current study). Surgical intervention for triple pathology cases anecdotally appears effective in achieving seizure control. © 2015 Elsevier Inc. All rights reserved.
1. Introduction
2. Methods and materials
The pathologic substrates underlying pharmacoresistent epilepsy have been well described and most commonly involve hippocampal sclerosis (in patients with temporal lobe epilepsy), focal cortical dysplasia, remote infarcts/contusional damage, and neoplasms [1-5]. In most patients who undergo surgical resection, an imaging abnormality or pathologic abnormality is identified grossly or upon microscopic examination, although there are a small percentage of cases in which no obvious pathologic or imaging findings are noted (so-called nonlesional cases) [6]. Occasionally, more than 1 pathology, which independently can be causative of epilepsy, may be identified in resected tissues, so-called dual pathology. These most commonly involve combinations of tumor and focal cortical dysplasia or hippocampal sclerosis and focal cortical dysplasia [7-11]. Only rare instances of triple pathology, where 3 potentially etiologic lesions coexist in the same patient, have been reported [12-15]. This article reports 2 cases of triple pathology in pediatric patients with a history of medical intractable epilepsy who underwent surgical resection of the epileptogenic focus.
Institutional review board approval was obtained before commencement of the study. The anatomic pathology files were searched for cases of hippocampal sclerosis diagnosed between January 2000 and December 2012. All such cases were reviewed to confirm a diagnosis of hippocampal sclerosis, using criteria outlined by the International League against Epilepsy (ILAE) group [16]. Three hundred forty-nine cases were identified. Of those cases, 2 patients had coexistent ganglioglioma and focal cortical dysplasia excised at the same time. Criteria for the diagnosis of ganglioglioma outlined by the World Health Organization (WHO) were used in classifying the tumors [17]. Classification of the focal cortical dysplasia patterns observed used the Palmini et al. [18] and more recent ILAE approaches [7]. Medical records were reviewed for pertinent clinical information. Ki-67 immunostaining (prediluted; Ventana, Tucson, AZ) was performed in each tumor; 1000 tumor cells from the area of the tumor with the most staining were assessed, and a labeling index was determined (ie, percentage of positive staining tumor cells). 3. Results 3.1. Patient 1
⁎ Corresponding author at: Department of Anatomic Pathology, L25, Cleveland Clinic, 9500 Euclid Ave, Cleveland, OH, 44195, USA. Tel.: +1 216 444 8805; fax: +1 216 445 6967. E-mail address: [email protected] (R.A. Prayson).
The patient was a 6-year-old, left-handed girl who presented at age 2 years with new-onset seizures. There was no history of birth or head
http://dx.doi.org/10.1016/j.anndiagpath.2015.07.003 1092-9134/© 2015 Elsevier Inc. All rights reserved.
Please cite this article as: Prayson RA, Gales JM, Coexistent ganglioglioma, focal cortical dysplasia, and hippocampal sclerosis (triple pathology) in chronic epilepsy, Ann Diagn Pathol (2015), http://dx.doi.org/10.1016/j.anndiagpath.2015.07.003
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R.A. Prayson, J.M. Gales / Annals of Diagnostic Pathology xxx (2015) xxx–xxx
trauma, infection, or infantile febrile seizures. Her seizures were of 2 types: tonic seizures and seizures marked by staring episodes and unresponsiveness. Seizures were localized by electroencephalogram studies to the left anterior mesial and basal temporal lobe. The patient was also diagnosed with oppositional defiant disorder. Initially, the seizures responded to antiepileptic medication (Tegretol). The physical examination was normal. Magnetic resonance imaging (MRI) studies showed abnormal signal on T2-weighted-Fluid-Attenuated Inversion Recovery images in the left parahippocampal gyrus and posterior hippocampus with a small cystic area and indistinct gray-white junction. No enhancement was noted. The possibility of a low-grade glioma with associated focal cortical dysplasia was raised. The patient underwent left temporal lobectomy with resection of mesial structures. Histologic sections from the hippocampus (totally submitted) showed loss of neurons and gliosis predominantly involving the CA1 and CA4 regions of the hippocampus, consistent with classic hippocampal sclerosis (ILAE type Ia) (Fig. 1A). A section from the totally submitted amygdala showed occasional collections of small round neurons (hamartia). Sections from the subtotally sampled left temporal lobe was marked by a focal area of increased cellularity composed of a proliferation of atypical astrocytic cells with an intermixed neuronal cell component, consistent with a ganglioglioma, WHO grade I (Fig. 1B). Dystrophic calcifications are present in the tumor. Mitotic activity, vascular proliferative changes, and necrosis were not seen. A Ki-67 labeling index of 0.6% was observed. The adjacent temporal lobe parenchyma was marked by mild focal cortical architectural organization, principally in a horizontal orientation, consistent with focal cortical dysplasia (Palmini et al. type IA, resembling an ILAE type Ib pattern) (Fig. 1C). Balloon cells, dysmorphic neurons, and neuronal cytomegaly were not observed in areas of focal cortical dysplasia. Focally, Chaslin gliosis (subpial gliosis) was observed. At the last known follow-up 20 months postoperatively, the patient was seizure free on antiepileptic medication. 3.2. Patient 2 The patient was a 9-year-old, left-handed man who presented with a new-onset, grand mal seizure at age 9 months. Seizures typically consisted of arrested activity with staring and deviation of the head and eyes to the right. Seizures were adequately controlled with medications for the first 2 years. There was no history of birth or head trauma, infection, or infantile febrile seizures. Electroencephalogram localized the seizures to the left temporal and occipital lobe regions. He was also diagnosed with attention deficit hyperactivity syndrome with a pervasive developmental disorder. An MRI done after the first seizure showed subtle enlargement of the posterior temporal-occipital region. Repeat MRI studies 5 years later showed increased T2/FLAIR signal in the posterior medial left temporal lobe, which was interpreted as most likely representing focal cortical dysplasia. A positron emission tomography scan showed severe hypometabolism in the left medial and posterior temporal lobe and left inferior and medial occipital lobe cortex. Histologic sections from the left hippocampus, which was totally submitted for pathologic examination, showed severe loss of neurons accompanied by gliosis in the CA1 and CA4 regions (severe hippocampal sclerosis, ILAE type Ib) (Fig. 2A). The left amygdala was totally submitted for pathologic examination and showed nonspecific gliosis and perivascular white matter atrophy. Sections from the subtotally submitted temporal and occipital lobe resection showed a focally microcystic neoplasm characterized by a proliferation of atypical appearing astrocytic cells intermixed with an atypical neuronal cell component (Fig. 2B). Foci of perivascular chronic inflammation, consisting primarily of benign appearing lymphocytes, and microcalcifications were observed in the tumor. Mitotic activity, vascular proliferative changes, and necrosis were not observed. The morphology of the tumor was consistent with that of a ganglioglioma, WHO grade I. A Ki-67 labeling
Fig. 1. Patient 1. Left hippocampus showing a prominent loss of neurons and gliosis in the CA1 or Sommer sector region (lower right) and a relative sparing of neurons in the CA2 region (top) (hematoxylin and eosin, original magnification × 50) (A). Patient 1. An abnormal clustering of ganglionic cells arranged against a hypercellular background resembling a low-grade astrocytoma in a ganglioglioma situated in the left temporal lobe (hematoxylin and eosin, original magnification ×200) (B). Patient 1. Superficial temporal lobe cortex adjacent to the tumor showing an absence of cortical layer 2, consistent with focal cortical dysplasia and subpial gliosis (hematoxylin and eosin, original magnification ×100) (C).
index of 0.9% was focally observed (Fig. 2C). The adjacent temporal and occipital lobe cortex showed focal architectural disorganization in both a horizontal and vertical orientation, consistent with a Palmini et al. type IA focal cortical dysplasia, resembling an ILAE type Ic pattern (Figs. 2D and E). Dysmorphic neurons, neuronal cytomegaly, and balloon cells were not noted in areas of focal cortical dysplasia. In addition, focal areas of Chaslin gliosis were observed. At last known follow-up 38 months after surgery, the patient was seizure free on antiepileptic medication.
Please cite this article as: Prayson RA, Gales JM, Coexistent ganglioglioma, focal cortical dysplasia, and hippocampal sclerosis (triple pathology) in chronic epilepsy, Ann Diagn Pathol (2015), http://dx.doi.org/10.1016/j.anndiagpath.2015.07.003
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Fig. 2. Patient 2. Left hippocampus showing a marked loss of neurons within the CA4 or endplate region (hematoxylin and eosin, original magnification ×100) (A). Patient 2. Left temporal lobe mass marked by focal microscystic change and a proliferation of atypical-appearing neuronal cells admixed with an atypical astrocytic cell proliferation (hematoxylin and eosin, original magnification ×100) (B). Patient 2. Ki-67 immunostain showing only rare positive staining tumor cell nuclei (original magnification ×200) (C). Patient 2. An area of focal cortical dysplasia near the ganglioglioma marked by a loss of cortical layer 2 and a malpositioning of neuronal cells (hematoxylin and eosin, original magnification ×200) (D). Patient 2. Another area adjacent to the tumor showing focal cortical dysplasia with columnar arrangements of neurons in the cortex (hematoxylin and eosin, original magnification ×200) (E).
4. Discussion The association of certain low-grade neoplasms with focal cortical dysplasia is well established. Certain glioneuronal neoplasms, which are common in the chronic epilepsy setting, notably gangliogliomas and dysembryoplastic neuroepithelial tumors, have been both well described as being frequently associated with adjacent focal cortical dysplasia [19-22]. Less commonly, reports of other less frequently encountered neoplasms in this setting, such as pleomorphic xanthoastrocytoma and angiocentric glioma, have been anecdotally described as sometimes being associated with focal cortical dysplasia [23,24]. The tumor-like meningioangiomatosis, which frequently presents with epilepsy, has
also recently been acknowledged to be sometimes associated as well [25]. In most of these cases, the histologic pattern of dysplasia often falls into the type I category [8]. The recent ILAE consensus classification for focal cortical dysplasia formally acknowledges these associations and designates these lesions as type IIIb [7]. The exact nature of these relationships is currently not completely understood, and a number of hypotheses have been suggested. The frequency of the coexistence, particularly with dysembryoplastic neuropepithelial tumors and in some series with gangliogliomas, suggests some sort of relationship. Perhaps the coexistent lesions represent different phenotypic appearances of a common disruption in development. Perhaps they represent opposite ends of a spectrum (diffuse vs
Please cite this article as: Prayson RA, Gales JM, Coexistent ganglioglioma, focal cortical dysplasia, and hippocampal sclerosis (triple pathology) in chronic epilepsy, Ann Diagn Pathol (2015), http://dx.doi.org/10.1016/j.anndiagpath.2015.07.003
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R.A. Prayson, J.M. Gales / Annals of Diagnostic Pathology xxx (2015) xxx–xxx
focal lesion). Perhaps one lesion gives rise to the other in certain circumstances or under certain genetic or environmental conditions. The clinical significance lies in the implication for surgical management and seizure outcomes. In most of the tumors, the neoplasm itself is electrically silent, and seizures are emanating from adjacent tissue [26]. Excision of the tumor alone likely leaves behind adjacent areas of focal cortical dysplasia, which may contribute to continued seizures or the development of recurrent seizures. The association of hippocampal sclerosis with focal cortical dysplasia is also well established [7]. The reported prevalence of this coexistence is variable and has ranged from rare to relatively common. No obvious etiology or clinicopathologic phenotype is associated with these cases, which is a source of continue conjecture in this area as to the precise nature of the coexistence [27]. The ILAE classification of focal cortical dysplasia formally recognized this association and denotes these cases as representing type IIIa dysplasia [7]. Whether the changes seen in this setting are acquired, that is, the hippocampal sclerosis lesion and focal cortical dysplasia result from reorganization (dysplasia) or injury resulting in hippocampal sclerosis, or these cases represent a distinct developmental abnormality whereby the hippocampal sclerosis develops secondary to chronic epilepsy resulting from the focal cortical dysplasia lesion is uncertain. The lack of clinical differences and postsurgical outcomes between hippocampal sclerosis and hippocampal sclerosis with focal cortical dysplasia patients would argue for a common etiology [28,29]. Only anecdotal prior case reports of triple pathology have been reported [30,13,12]. In 2009, Samura et al. reported a case of cavernoma associated with focal cortical dysplasia and hippocampal sclerosis presenting in a 33-year-old woman who had seizures since age 2 years arising in the right frontotemporal region. The focal cortical dysplasia was marked by the presence of dysmorphic neurons and an absence of balloon cells. The patient was seizure free 12 months after surgery on antiepileptic medication. Maciunas et al [30] reported a similar case of cavernoma associated with focal cortical dysplasia and hippocampal sclerosis in a 63-year-old man who had seizures staring at age 25 years culminating in a resection of the left anterior temporal lobe, amygdala, and hippocampus. The dysplasia resembled a Palmini et al. type IB pattern. The patient had been seizure free 18 months after surgery; it is unclear whether the patient was still on antiseizure medication. Cheong et al. [13] reported a case of a 27-year-old man who was diagnosed with seizures at age 16 years and who developed remote ischemic changes; Rasmussen encephalitis; and type II dysplasia, not further delineated, in the right frontotemporal lobe region. The patient was reported to be seizure free after surgery, but no interval of time was reported, or whether the patient was still taking antiepileptic medications. The only case of triple pathology involving a tumor was reported by Yang et al [12] in 2013. They presented a case of a 29-year-old man who presented with recurrent seizures for a 4-year period and who underwent resection of the right anterior temporal lobe, hippocampus, and amygdala. Histologic examination of resected tissues revealed a ganglioglioma, WHO grade I, focal cortical dysplasia (type IIA), and hippocampal sclerosis. The patient had been seizure free on antiepileptic medications for the 8 months after surgery. The 2 cases reported in the current series were similar in that they also involved the temporal lobe. The coexistent dysplasia patterns were ILAE type I/Palmini et al. type I lesions, phenotypically similar to most cases of dysplasia seen with low-grade glioneuronal tumors and hippocampal sclerosis. Both of the current cases have been seizure free on antiepileptic medications for 20 and 38 months, suggesting that good seizure outcome, at least in the short term, may be attainable in these cases, despite the presence of triple pathology. Long-term prognosis may be dependent on the extent of the focal cortical dysplasia in these patients, whether dysplasia tissue
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Please cite this article as: Prayson RA, Gales JM, Coexistent ganglioglioma, focal cortical dysplasia, and hippocampal sclerosis (triple pathology) in chronic epilepsy, Ann Diagn Pathol (2015), http://dx.doi.org/10.1016/j.anndiagpath.2015.07.003