Dysembryoplastic Neuroepithelial Tumors Share with Pleomorphic Xanthoastrocytomas and Gangliogliomas BRAFV600E Mutation and Expression

Pediatric cortical glioneuronal benign tumors mainly include gangliogliomas (GG) [differential diagnoses pilocytic astrocytomas (PA) and pleomorphic xanthoastrocytomas (PXA)] and dysembryoplastic neuroepithelial tumor (DNT). DNT include the specific form and the controversial non‐specific form that lack the specific glioneuronal element. Our aims were to search for BRAF^V600E mutation and CD34 expression in DNT, PXA, GG and PA to correlate BRAF^V600E mutation with BRAF^V600E expression and to evaluate their diagnostic and prognostic values. Ninety‐six children were included. BRAF^V600E mutation was studied by sequencing and immunohistochemistry; CD34 expression was analyzed by immunohistochemistry. BRAF^V600E mutation was detected in PXA (60%), GG (38.7%), DNT (30%, including 3/11 specific and 3/9 non‐specific forms) and PA (12.5%). BRAF^V600E expression was recorded in PXA (60%), GG (45.2%) and DNT (30%). CD34 expression was recorded in PXA (60%), GG (58.1%), DNT (25%) and PA (12.5%). Neither CD34 expression nor BRAF^V600E status was predictive of prognosis, except for PA tumors where CD34 expression was associated with a shorter overall survival. In conclusion, DNT shared with PXA and GG, BRAF^V600E mutation and/or CD34 expression, which represent molecular markers for these tumors, and we recommend searching for CD34 expression and BRAF^V600E mutation in all DNT, especially the non‐specific forms.     

Sturge–Weber Syndrome Is Associated with Cortical Dysplasia ILAE Type IIIc and Excessive Hypertrophic Pyramidal Neurons in Brain Resections for Intractable Epilepsy

Sturge–Weber syndrome (SWS) is a rare syndrome characterized by capillary‐venous malformations involving skin and brain. Many patients with SWS also suffer from drug‐resistant epilepsy. We retrospectively studied a series of six SWS patients with epilepsy and extensive neurosurgical resections. At time of surgery, the patients' age ranged from 11 to 35 years (with a mean of 20.2 years). All surgical specimens were well preserved, which allowed a systematic microscopical inspection utilizing the 2011 ILAE classification for focal cortical dysplasia (FCD). Neuropathology revealed dysmorphic‐like neurons with hypertrophic cell bodies reminiscent to those described for FCD type IIa in all cases. However, gross architectural abnormalities of neocortical layering typical for FCD type IIa were missing, and we propose to classify this pattern as FCD ILAE type IIIc. In addition, our patients with earliest seizure onset also showed polymicrogyria (PMG; n = 4). The ictal onset zones were identified in all patients by subdural electrodes, and these areas always showed histopathological evidence for FCD type IIIc. Four out of five patients had favorable seizure control after surgery with a mean follow‐up period of 1.7 years. We concluded from our study that FCD type IIIc and PMG are frequently associated findings in SWS. FCD type IIIc may play a major epileptogenic role in SWS and complete resection of the associated FCD should be considered a prognostic key factor to achieve seizure control.     

Neuropathological Findings in Intractable Epilepsy: 435 Chinese Cases

The number of patients with intractable epilepsy undergoing surgical management in China is increasing rapidly. We retrospectively reviewed 435 consecutive cases of intractable epilepsy receiving surgical resection from 2005 to 2008 in our hospital, looking specifically at the neuropathological findings. The three most common causes of intractable epilepsy were focal cortical dysplasia (FCD; 52.9%), scar lesions (22.8%) and brain tumors (11.7%). Hippocampal sclerosis was identified in 74 cases (17.0%), although most of these were accompanied by dual pathology with FCD (especially Palmini type IB), scar lesions or tumors. Among FCD cases, Palmini type I lesions are the most frequently observed abnormality, with a preferred location in the temporal lobe (60.1%) and often accompanied by dual pathology. In contrast, Palmini type II FCD lesions occurred predominantly in the frontal regions and with a lower age of onset. Most tumors were mixed neuronal–glial tumors, mainly ganglioglioma (19 cases) and dysembryoplastic neuroepithelial tumor (10 cases), with a trend toward a temporal location and usually accompanied by cortical dysplasia in the peritumor area. Our data on the neuropathology of intractable epilepsy in China show that glioneuronal lesions are the most prominent cause of intractable epilepsy, and this is consistent with reports from other countries.     

难治性癫痫相关脑肿瘤的临床病理学研究

目的 探讨难治性癫痫相关脑肿瘤的临床病理学特征.方法 选择 2005年1月至2008年4月期间在首都医科大学宣武医院接受难治性癫痫致痫灶手术切除治疗并经病理诊断为脑肿瘤患者的临床、影像以及病理学资料35例进行回顾性分析.结果 35例患者的癫痫平均发病年龄为14.3岁,平均病程8.6年,94.3%(33/35)的患者经头颅核磁共振(MRI)检查可见异常信号表现.组织学分型:神经节细胞胶质瘤19例(WHO Ⅰ级13例,WHOⅡ级6例),胚胎发育不良性神经上皮瘤3例(WHO Ⅰ级),多形性黄色瘤型星形细胞瘤3例(WHO Ⅱ级),弥漫性星形细胞瘤(WHO Ⅱ级)、少突星形细胞瘤(WHO Ⅱ级)、血管中心性胶质瘤(WHO Ⅰ级)和脑膜血管瘤病各1例,另有6例病变的组织学形态介于胶质神经元错构性病变和混合性神经元-胶质肿瘤之间.上述肿瘤多位于颞叶(27/35),多数同时伴有局灶性皮质发育不良的双重病理改变.免疫组织化学染色可见CD34显著表达于神经节细胞胶质瘤等病例.结论 表现为难治性癫痫的脑肿瘤多为位于颞叶且生长缓慢的混合性神经元-胶质肿瘤.观察到一组形态学上介于错构性病变和混合性神经元-胶质肿瘤之间的具有过渡特征的病变,这些错构性病变和肿瘤在组织形态学上体现的连续性以及良好的生物学行为提示了它们具有相同或相似的发生来源和发病机制,由此提出胶质神经元混合性病变的疾病谱概念.     

BRAF V600E Mutation Is Associated with mTOR Signaling Activation in Glioneuronal Tumors

BRAF V600E mutations have been recently reported in glioneuronal tumors (GNTs). To evaluate the expression of the BRAF V600E mutated protein and its association with activation of the mammalian target of rapamycin (mTOR) pathway, immunophenotype and clinical characteristics in GNTs, we investigated a cohort of 174 GNTs. The presence of BRAF V600E mutations was detected by direct DNA sequencing and BRAF V600E immunohistochemical detection. Expression of BRAF‐mutated protein was detected in 38/93 (40.8%) gangliogliomas (GGs), 2/4 (50%) desmoplastic infantile gangliogliomas (DIGs) and 23/77 (29.8%) dysembryoplastic neuroepithelial tumors (DNTs) by immunohistochemistry. In both GGs and DNTs, the presence of BRAF V600E mutation was significantly associated with the expression of CD34, phosphorylated ribosomal S6 protein (pS6; marker of mTOR pathway activation) in dysplastic neurons and synaptophysin (P < 0.05). In GGs, the presence of lymphocytic cuffs was more frequent in BRAF‐mutated cases (31 vs. 15.8%; P = 0.001). The expression of both BRAF V600E and pS6 was associated with a worse postoperative seizure outcome in GNT (P < 0.001). Immunohistochemical detection of BRAF V600E‐mutated protein may be valuable in the diagnostic evaluation of these glioneuronal lesions and the observed association with mTOR activation may aid in the development of targeted treatment involving specific pathogenic pathways.     

Tissue plasminogen activator and urokinase plasminogen activator in human epileptogenic pathologies

A growing body of evidence demonstrates the involvement of plasminogen activators (PAs) in a number of physiologic and pathologic events in the CNS. Induction of both tissue plasminogen activator (tPA) and urokinase plasminogen activator (uPA) has been observed in different experimental models of epilepsy and tPA has been implicated in the mechanisms underlying seizure activity. We investigated the expression and the cellular distribution of tPA and uPA in several epileptogenic pathologies, including hippocampal sclerosis (HS; n=6), and developmental glioneuronal lesions, such as focal cortical dysplasia (FCD, n=6), cortical tubers in patients with the tuberous sclerosis complex (TSC; n=6) and in gangliogliomas (GG; n=6), using immuno-cytochemical, western blot and real-time quantitative PCR analysis. TPA and uPA immunostaining showed increased expression within the epileptogenic lesions compared to control specimens in both glial and neuronal cells (hippocampal neurons in HS and dysplastic neurons in FCD, TSC and GG specimens). Confocal laser scanning microscopy confirmed expression of both proteins in astrocytes and microglia, as well as in microvascular endothelium. Immunoblot demonstrated also up-regulation of the uPA receptor (uPAR; P<0.05). Increased expression of tPA, uPA, uPAR and tissue PA inhibitor type mRNA levels was also detected by PCR analysis in different epileptogenic pathologies (P<0.05). Our data support the role of PA system components in different human focal epileptogenic pathologies, which may critically influence neuronal activity, inflammatory response, as well as contributing to the complex remodeling of the neuronal networks occurring in epileptogenic lesions.     

Cell injury and Premature Neurodegeneration in Focal Malformations of Cortical Development

Several lines of evidence suggest that cell injury may occur in malformations of cortical development associated with epilepsy. Moreover, recent studies support the link between neurodevelopmental and neurodegenerative mechanisms. We evaluated a series of focal cortical dysplasia (FCD, n = 26; type I and II) and tuberous sclerosis complex (TSC, n = 6) cases. Sections were processed for terminal deoxynucleotidyl transferase‐mediated 2′‐deoxyuridine 5′‐triphosphate nick‐end labeling (TUNEL) labeling and immunohistochemistry using markers for the evaluation of apoptosis signaling pathways and neurodegeneration‐related proteins/pathways. In both FCD II and TSC specimens, we observed significant increases in both TUNEL‐positive and caspase–3‐positive cells compared with controls and FCD I. Expression of β‐amyloid precursor protein was observed in neuronal soma and processes in FCD II and TSC. In these specimens, we also observed an abnormal expression of death receptor‐6. Immunoreactivity for phosphorylated tau was only found in older patients with FCD II and TSC. In these cases, prominent nuclear/cytoplasmic p62 immunoreactivity was detected in both dysmorphic neurons and balloon/giant cells. Our data provide evidence of complex, but similar, mechanisms of cell injury in focal malformations of cortical development associated with mammalian target of rapamycin pathway hyperactivation, with prominent induction of apoptosis‐signaling pathways and premature activation of mechanisms of neurodegeneration.     

Epstein‐Barr virus frequency in primary central nervous system lymphomas in Turkey

Primary central nervous system (CNS) lymphomas are rare neoplasms which are usually not associated with Epstein‐Barr virus (EBV) in immunocompetent patients. The aim of this study was to investigate the incidence of EBV in primary CNS lymphomas in the Turkish population. Thirty‐two primary CNS lymphomas diagnosed according to the WHO 2008 criteria were included in this study. The presence of EBV small ribonucleic acids was investigated by in situ hybridization using EBV encoded small RNA oligonucleotides. The expression of CD10, Bcl‐6, MUM‐1/IRF‐4, Bcl‐2, and Ki‐67 were evaluated using immunohistochemistry. The patient cohort included 20 male patients and 12 female patients with a median age of 53.5 years (range 13–75). Seven (22%) of cases were classified as germinal center (GC) and 25 (78%) cases as non‐GC phenotype according to the Hans criteria. Twenty‐six (81%) of the cases showed strong Bcl‐2 expression and the median Ki‐67 index was 78%. EBV expression was observed in four primary CNS lymphoma cases (12.5%). Most primary CNS lymphomas show non‐GC phenotype with high Bcl‐2 expression and high proliferative rate. The incidence of EBV in primary CNS lymphomas from Turkey appears to be higher than that observed in the Western countries.     

癫痫相关局灶性皮质发育不良的临床病理学研究

目的研究癫痫相关局灶性皮质发育不良（FCD）的临床病理学特征。方法对38例2005年在北京宣武医院接受致痫灶外科手术切除治疗并临床病理诊断为FCD患者的临床资料、神经影像学以及病理学资料进行回顾性分析。结果38例患者的平均发病年龄为9．2岁,平均病程为11．9年,发作形式以复杂部分性发作为主。神经影像学检查有21例可见海马硬化、灰质异常信号等改变。组织学具体分型为：FCDⅠA型3例,FCDⅠB型20例,FCDⅡA型5例以及FCDⅡB型5例,另有5例被诊断为轻微皮质发育不良（mild MCD）。从部位来看,FCDⅡ型病变多见于颞叶以外的脑叶（8／10）,尤以额叶多见（5／8）。具有双重病理改变的5例均为FCDⅠB型。在免疫组织化学染色,巨大神经元、未成熟神经元、形态异常神经元及白质内异位神经元均可由NeuN清晰的标记出来。少数气球细胞呈nestin阳性表达。结论FCD是难治性癫痫的常见病理组织学所见,其中又以FCDIB型最为多见,并且可伴有海马硬化。FCDⅠ型和Ⅱ型有着不同的临床病理学以及细胞病理学形特征。     

CD34 and microtubule-associated protein 2 expression in dysembryoplastic neuroepithelial tumours with an emphasis on dual expression in non-specific types

Sung C O, Suh Y‐L & Hong S‐C
(2011) Histopathology 59 , 308–317 CD34 and microtubule‐associated protein 2 expression in dysembryoplastic neuroepithelial tumours with an emphasis on dual expression in non‐specific types Aims: Three histological variants of dysembryoplastic neuroepithelial tumour (DNT) have been described, namely, simple, complex and non‐specific. However, the concept of non‐specific variants of DNT remains controversial, because they cannot be accurately distinguished by histological findings alone from ordinary gliomas. The aim was to characterize further the non‐specific histological forms of DNT. Methods and results: Forty‐one DNTs classified as three histological forms were investigated with CD34 and microtubule‐associated protein 2 (MAP2) immunohistochemistry. CD34 immunoreactivity was more frequently observed in non‐specific DNT types (16/18 cases; 88.9%) than in classic types (6/23 cases; 26.1%) (P < 0.001). Peritumoral CD34 expression of non‐neoplastic cells was significantly associated with CD34‐positive tumours (20/22 cases; 90.9%) than with CD34‐negative tumours (3/19 cases; 15.8%) (P < 0.001). MAP2 positivity in oligodendroglia‐like cells or glial elements was significantly different between classic types and non‐specific types (P = 0.025). CD34 and MAP2 immunoreactivities were significantly more frequent in non‐specific types (83.3%) than in simple (10%) and complex forms (30.8%) (P < 0.001). Conclusions: Non‐specific DNTs are glioneuronal tumours that have a heterogeneous population of cells with more immature neuronal and glial phenotypes. Furthermore, with regard to practical implications, combined analysis of CD34 and MAP2 is useful in distinguishing DNTs from particularly diagnostically challenging mimics.     

Autophagy and Bcl‐2/BNIP3 death regulatory pathway in non‐small cell lung carcinomas

We recently showed that non‐small cell lung carcinomas (NSCLCs) are of dismal prognosis when encompassing accelerated autophagic activity. The regulation of this abnormally functioning degradation system and its association with hypoxia and apoptosis in lung carcinoma patients is unexplored. In this study we used 115 NSCLC tissues to examine the immunohistochemical expression of four distinct molecules – the major regulator of autophagy Beclin 1, the anti‐apoptotic and anti‐autophagic protein Bcl‐2, the pro‐apoptotic and pro‐autophagic protein BNIP3, and a marker of hypoxia and glucolysis, the glucose transporter Glut 1. Most cases showed reduced reactivity for Beclin 1 (62%) and Bcl‐2 (82%) proteins, almost half of our sample revealed strong BNIP3 expression (57%), whereas most of the carcinomas strongly expressed Glut 1 antigen (71%). Beclin 1 expression showed no association with survival. Bcl‐2 positivity was a marker of good prognosis (p = 0.04), whereas BNIP3 (p = 0.0004) and Glut 1 (p = 0.03) expression correlated with poor outcome in Stage I disease. Autophagic status was negatively associated with Bcl‐2 (p = 0.0006), but positively with Glut 1 expression (p = 0.001). In conclusion, the accelerated autophagic status in NSCLC is unrelated to Beclin 1 and BNIP3 expression, but does show significant association with Bcl‐2 reactivity. Furthermore, we showed important correlations between glucolysis and autophagy, guiding new pathways in future lung carcinoma research.     

Combined Ex Vivo 9.4T MRI and Quantitative Histopathological Study in Normal and Pathological Neocortical Resections in Focal Epilepsy

High‐resolution magnetic resonance imaging (MRI) may improve the preoperative diagnosis of focal cortical dysplasia (FCD) in epilepsy. Quantitative 9.4T MRI was carried out (T1, T2, T2* and magnetization transfer ratio) on 13 cortical resections, representing pathologically confirmed FCD (five cases) and normal cortex. Quantitative immunohistochemistry for myelination (myelin basic protein/SMI94), neuronal populations [microtubule‐associated protein 2 (MAP2), neurofilament (SMI31, SMI32), synaptophysin, NeuN, calbindin], reactive glia (GFAP), microglia (CD68) and blood–brain barrier permeability (albumin) was carried out in 43 regions of interest (ROI) from normal and abnormal white matter and cortex. MRI was spatially aligned and quantitative analysis carried out on corresponding ROI. Line profile analysis (LPA) of intensity gradients through the cortex was carried out on MRI and immunostained sections. An inverse correlation was noted between myelin/SMI94 and T1, T2 (P < 0.005) and T2* (P < 0.05; Spearman's correlation) and a positive correlation between neuronal MAP2 and T1 (P < 0.005) and T2* (P < 0.05) over all ROI. Similar pathology–MRI correlations were observed for histologically unremarkable white matter ROI only. LPA showed altered gradient contours in regions of FCD, reflecting abnormal cortical lamination and myelo‐architecture, including a preoperatively undetected FCD case. This study demonstrates the ability of quantitative 9.4T MRI to detect subtle differences in neuronal numbers and myelination in histologically normal appearing white matter and LPA in the evaluation of cortical dyslamination. These methods may be translatable to the in vivo detection of mild cortical malformations.     

Prostate‐specific membrane antigen expression in tumor‐associated vasculature of breast cancers

Prostate‐specific membrane antigen (PSMA) has been found to be expressed in the tumor‐associated neovasculature of multiple solid tumor types including breast cancers. However, thus far, the number of cases studied from some tumor types has been limited. In this study, we set out to assess PSMA expression in the tumor‐associated vasculature associated with invasive breast carcinomas in a sizable cohort of patients. One hundred and six patients with AJCC stage 0‐IV breast cancer were identified. Ninety‐two of these patients had primary breast cancer [invasive breast carcinoma with or without co‐existing ductal carcinoma in situ (DCIS) (74) or DCIS alone (18)]. In addition, 14 patients with breast cancer metastases to the brain were identified. Immunohistochemical staining for PSMA and CD31 was performed on parallel representative tumor sections in each case. Tumor‐associated vascular endothelial cell PSMA immunoreactivity was semi‐quantitatively assessed based on two parameters: overall percent of endothelial positivity and staining intensity. PSMA expression for tumor‐associated vascular endothelial cells was scored 0 if there was no detectable PSMA expression, 1 if PSMA staining was detectable in 5–50%, and 2 if PSMA expression was positive in >50% of microvessels. CD 31 staining was concurrently reviewed to confirm the presence of vasculature in each case. Tumor‐associated vasculature was PSMA‐positive in 68/92 (74%) of primary breast cancers and in 14/14 (100%) of breast cancers metastatic to brain. PSMA was not detected in normal breast tissue or carcinoma cells. All but 2 cases (98%) showed absence of PSMA expression in normal breast tissue‐associated vasculature. The 10‐year overall survival was 88.7% (95% CI = 80.0%, 93.8%) in patients without brain metastases. When overall survival (OS) was stratified based on PSMA score group, patients with PSMA scores of 0, 1, and 2 had 10‐year OS of 95.8%, 96.0%, and 79.7%, respectively (p = 0.12). When PSMA scores of 0 and 1 were compared with 2, there was a statistically significant difference in OS (96.0% vs 79.7%, respectively, p = 0.05). Patients with a PSMA score of 2 had a significantly higher median tumor size compared with patients in the lower PSMA score groups (p = 0.04). Patients with higher nuclear grade were more likely to have a PSMA score of 2 compared with patients with lower nuclear grade (p < 0.0001). Patients with a PSMA score of 2 had a significantly higher median Ki‐67 proliferation index compared with patients in the lower PSMA score groups (p < 0.0001). Patients with estrogen receptor (ER)‐negative tumors were more likely to have a PSMA score of 2 compared with patients with ER‐positive tumors (p < 0.0001). Patients with progesterone receptor (PR)‐negative tumors were more likely to have a PSMA score of 2 compared with patients with PR‐positive tumors (p = 0.03). No significant association was observed between PSMA score group status and lymph node involvement (p = 0.95). Too little variability was present in Human epidermal growth factor receptor‐2 (Her2/neu) amplified tumors to correlate with PSMA score group status. To date, this is the first detailed assessment of PSMA expression in the tumor‐associated vasculature of primary and metastatic breast carcinomas. Further studies are needed to evaluate whether PSMA has diagnostic and/or potential therapeutic value.     

Impaired oligodendroglial turnover is associated with myelin pathology in focal cortical dysplasia and tuberous sclerosis complex

Conventional antiepileptic drugs suppress the excessive firing of neurons during seizures. In drug‐resistant patients, treatment failure indicates an alternative important epileptogenic trigger. Two epilepsy‐associated pathologies show myelin deficiencies in seizure‐related brain regions: Focal Cortical Dysplasia IIB (FCD) and cortical tubers in Tuberous Sclerosis Complex (TSC). Studies uncovering white matter‐pathology mechanisms are therefore urgently needed to gain more insight into epileptogenesis, the propensity to maintain seizures, and their associated comorbidities such as cognitive defects. We analyzed epilepsy surgery specimens of FCD IIB (n = 22), TSC (n = 8), and other malformations of cortical development MCD (n = 12), and compared them to autopsy and biopsy cases (n = 15). The entire lesional pathology was assessed using digital immunohistochemistry, immunofluorescence and western blotting for oligodendroglial lineage, myelin and mTOR markers, and findings were correlated to clinical parameters. White matter pathology with depleted myelin and oligodendroglia were found in 50% of FCD IIB and 62% of TSC cases. Other MCDs had either a normal content or even showed reactive oligodendrolial hyperplasia. Furthermore, myelin deficiency was associated with increased mTOR expression and the lower amount of oligodendroglia was linked with their precursor cells (PDGFRa). The relative duration of epilepsy (normalized to age) also correlated positively to mTOR activation and negatively to myelination. Decreased content of oligodendroglia and missing precursor cells indicated insufficient oligodendroglial development, probably mediated by mTOR, which may ultimately lead to severe myelin loss. In terms of disease management, an early and targeted treatment could restore normal myelin development and, therefore, alter seizure threshold and improve cognitive outcome.     

The adaptor protein SAP regulates type II NKT‐cell development,cytokine production,and cytotoxicity against lymphoma

CD1d‐restricted NKT cells represent a unique lineage of immunoregulatory T cells that are divided into two groups, type I and type II, based on their TCR usage. Because there are no specific tools to identify type II NKT cells, little is known about their developmental requirements and functional regulation. In our previous study, we showed that signaling lymphocytic activation molecule associated protein (SAP) is essential for the development of type II NKT cells. Here, using a type II NKT‐cell TCR transgenic mouse model, we demonstrated that CD1d‐expressing hematopoietic cells, but not thymic epithelial cells, meditate efficient selection of type II NKT cells. Furthermore, we showed that SAP regulates type II NKT‐cell development by controlling early growth response 2 protein and promyelocytic leukemia zinc finger expression. SAP‐deficient 24αβ transgenic T cells (24αβ T cells) exhibited an immature phenotype with reduced Th2 cytokine‐producing capacity and diminished cytotoxicity to CD1d‐expressing lymphoma cells. The impaired IL‐4 production by SAP‐deficient 24αβ T cells was associated with reduced IFN regulatory factor 4 and GATA‐3 induction following TCR stimulation. Collectively, these data suggest that SAP is critical for regulating type II NKT cell responses. Aberrant responses of these T cells may contribute to the immune dysregulation observed in X‐linked lymphoproliferative disease caused by mutations in SAP.     

Surgical pathologic findings of extratemporal-based intractable epilepsy: a study of 133 consecutive resections

BACKGROUND: Surgical management of intractable epilepsy continues to be important in select cases to achieve seizure control. DESIGN: This study retrospectively reviews the pathologic findings in 133 consecutive cases of extratemporal lobe epilepsy experienced during a 17-year period. RESULTS: The study group consists of 133 patients (78 males) who underwent extratemporal lobe resection for epilepsy at a mean age of 21.1 years (range, 3 months to 57 years). In 50 patients (37.6%), cortical dysplasia (neuronal migration abnormalities) was identified. The most common patterns of dysplasia observed included diffuse architectural disorganization in 46 cases, neuronal cytomegaly in 30 cases, increased numbers of molecular layer neurons in 30 cases, and balloon cells in 18 cases. Tumors were identified in 37 cases (27.8%) and included 13 astrocytomas, 7 gangliogliomas, 6 dysembryoplastic neuroepithelial tumors, 6 glioneuronal hamartomas, 4 oligodendrogliomas, and 1 oligoastrocytoma (mixed glioma). Twenty-four resections (18%) showed evidence of remote ischemic damage or infarct. Neuronal heterotopia was identified in 59 resection specimens (44.4%). Other less common findings included vascular malformations in 4 patients (3.0%), Sturge-Weber malformations in 3 patients (2.3%), and Rasmussen encephalitis in 2 patients (1.5%). Two patients were known to have tuberous sclerosis. In 23 resection specimens (17.3%), no significant pathologic finding was identified. Coexistent cortical dysplasia and tumor were seen in 10 cases and coexistent dysplasia and infarct or remote ischemic damage in 11 cases. CONCLUSION: This series demonstrates that most patients with extratemporal lobe epilepsy have significant histopathologic findings, which most frequently include cortical dysplasia, tumor, or evidence of remote ischemic damage or infarct. Coexistent pathologic findings were present in a significant minority of cases (16.5%).     

Pi3K-mTOR Signaling and AMOG Expression in Epilepsy-associated Glioneuronal Tumors

Gangliogliomas (GGs) and dysembryoplastic neuroepithelial tumors (DNTs) represent the most frequent type of neoplasms in pediatric medically intractable epilepsy. Several data suggest a pathogenetic relationship between GGs and other glioneuronal malformations of cortical development (MCDs), including activation of the Pi3K-mTOR signaling pathway. To further reveal these pathogenetic similarities, we investigated immunocytochemically the expression of phosphorylated (p)-PDK1, p-AKT, p-mTOR, p-4E-BP1, p-eIF4G, p-p70S6K and p-S6, the effector proteins ERM (ezrin/radixin/moesin) and the pathway regulator AMOG (adhesion molecule on glia) in both GGs and DNTs. Components of the Pi3K-mTOR signaling pathway were observed in a higher percentage of neuronal cells in GGs compared with control cortex. In DNTs, the expression of these components was low and comparable with the expression in control samples. Strong immunoreactivity for ERM was observed in GGs, but not in DNTs. Additionally, AMOG was strongly expressed within GGs (but not in DNTs) in CD34-positive precursor cells. These findings support the previously suggested pathogenic relationship between GG and MCDs concerning activation of the Pi3K-mTOR signaling pathway and suggest a different pathogenetic origin for DNTs. The strong expression of AMOG within the precursor cells of GG may represent an additional marker for the diagnostic evaluation of these glioneuronal lesions.     

CD34+ megakaryocytes (≥30%) are associated with megaloblastic anaemia and non‐acute myeloid neoplasia

Insuasti‐Beltran G, Steidler N L, Kang H & Reichard K K
(2012) Histopathology  61, 694–701 CD34+ megakaryocytes (≥30%) are associated with megaloblastic anaemia and non‐acute myeloid neoplasia Aims: To evaluate the sensitivity and specificity of CD34 staining of megakaryocytes (MKs), in order to distinguish non‐neoplastic and neoplastic bone marrows (BMs). Methods and results: Three hundred BMs (120 non‐neoplastic and 180 neoplastic) were evaluated for percentage and intensity of CD34 staining of MKs. The selected non‐neoplastic cases included anaemia, autoimmune conditions, immune thrombocytopenia (ITP), and staging BMs. The neoplastic cases included myelodysplastic syndromes and/or myeloproliferative neoplasms (MDS, MPN, MDS/MPN). Eight per cent of non‐neoplastic (9/120) cases and 13% of neoplastic (24/180) cases showed ≥30% CD34+ MKs, and these were essentially restricted to cases of megaloblastic anaemia (MBA) and non‐acute myeloid neoplasms. The finding of ≥30% CD34+ MKs did not distinguish between categories of non‐acute myeloid neoplasms. MDS cases with ≥30% CD34+ MKs had lower platelet counts than cases with <30% (P = 0.03). Conclusions: In complex BM cases, the presence of ≥30% CD34+ MKs constitutes a potentially useful diagnostic tool with which to distinguish non‐acute myeloid neoplasms and MBA from non‐MBA reactive conditions, for minimal additional cost.