The molecular genetics of meningiomas and genotypic/phenotypic correlations

The WHO classification divides meningiomas in three grades. In grade 1 tumors, by far the most common (90 p. cent), inactivation of the NF2 gene (associated to the loss of chromosome 22) is the most frequent alteration. However, a subset of grade 1 meningiomas does not involve the NF2 gene and is less likely to evolve towards higher grade tumors. After NF2 inactivation, additional events may occur and are related to greater aggressiveness, such as loss of 1p, 14q, 10 q and 9p chromosomes, reactivation of telomerase, inactivation of the p16/CDKN2A gene. All these alterations are much more frequent in grades 2 (atypical) and 3 (malignant) of the WHO classification. In addition to reviewing the available literature, we pooled together the individual cases in order to refine the correlation between genotype and phenotype (histological grading, location) and to propose a model for tumoral progression of meningiomas.     

Charcot-Marie-Tooth disease (CMT): distinctive phenotypic and genotypic features in CMT type 2

Charcot-Marie-Tooth disease (CMT), or hereditary motor and sensory neuropathy (HMSN), includes two main subtypes of CMT1/HMSN I (demyelinating), and CMT2/HMSN II (axonal). Further heterogeneity has been demonstrated by genetic molecular studies, with at least four responsible genes for CMT1. As for CMT2, a mutation in the neurofilament-light (NF-L) gene has been identified in a single family, and other CMT2 loci have been mapped. We propose a clinical classification of the CMT2 phenotypes, and review the features of the identified CMT2 genotypes. The following main subtypes of CMT2 are considered in the phenotype classification: classical CMT2, the variants of CMT2 showing atypical features that may represent either variance in the classical CMT2 phenotype or separate entities; CMT2 plus, i.e. complex forms with involvement of additional neural structures. The recognized CMT2 genotypes include: CMT2A (mapped to chromosome 1p35-36); CMT2B (3q13-22); CMT2C (with vocal cord paresis); CMT2D (7p14); CMT2E, related to a mutation in the NF-L gene on chromosome 8p21; proximal CMT2, or HMSN P (3q13.1); CMT2 with MPZ mutations; autosomal recessive CMT2 (1q21.2-q21.3); agenesis of the corpus callosum with sensorimotor neuronopathy (15q13-q15); CMT2 X-linked with deafness and mental retardation (Xq24-q26). The identified genotypes may correspond to previously described clinical subtypes of CMT2. In particular, classical CMT2 presents in association with NF-L gene mutation, in the only CMT2 family with known gene mutation, and in CMT2A patients. However, the features of classical CMT2 have been paradoxically reported also in families with MPZ mutation, and conversely several CMT2 families are not linked to the known CMT2 loci. Further cloning of the CMT2 genes will ultimately shed light on the pathogenic mechanism(s) implicated in the process of axonal degeneration, shared by the different CMT2 genotypes.     

The phenotypic and genotypic features of a Scottish cohort with McArdle disease

This retrospective study evaluated the phenotypic and genotypic features of 14 patients with McArdle disease attending the West of Scotland adult muscle clinic. Although all patients experienced exercise-induced cramps, exercise intolerance and hyperCKaemia, only 71% (n = 10) experienced the second wind phenomenon, rhabdomyolysis and/or myoglobinuria. We observed a high rate of fixed muscle weakness (50%; n = 7), coronary artery disease (36%; n = 5), and psychological comorbidity (50%; n = 7). Although 79% had symptom onset in the first decade of life, the mean age at presentation and at genetic diagnosis was 43.8 years and 47.7 years, respectively. 93% had at least one copy of the common PYGM pathogenic variant, c.148C > T, p.(Arg50*), with 50% (n = 7) of the cohort being homozygous. Our cohort highlights the phenotypic variability seen in McArdle disease and underscores the potential for late-onset presentations. It emphasises the need for improved awareness and recognition of this condition amongst neurologists, rheumatologists and general physicians. A history of exercise intolerance and second wind phenomenon may not always be volunteered by the patient, underscoring the need to ask specific questions in clinic to extrapolate the relevant symptoms in this patient cohort.     

Medulloblastoma: clinicopathologic evaluation of 42 pediatric cases

Purpose  The aim of this study was to assess the prognostic value of MIB-1 and p53 in the pediatric medulloblastoma group. Materials and method  Forty-two pediatric medulloblastoma cases diagnosed in a single institution during the past 10 years were evaluated. Follow-up data were available for 35 patients. Results  The immunoreactivity of MIB-1 ranged from 10% to 95%; p53 immunoreactivity was found in five cases. Of the 35 patients with follow-up, 34 patients received a combination of chemotherapy and radiotherapy, while one received chemotherapy alone. The follow-up period ranged from 5 to 64 months. Of the 35 patients, 21 were alive without any evidence of recurrent disease, three were alive with evidence of recurrent disease and 11 died of disease during follow-up. The mean survival for these 11 patients was 21.9 ± 10.4 months. Of the 35 cases, 16 had MIB-1 value of 25% or lower and 19 had a value of 26% or more. Of the 16 cases with low MIB-1 value, six died of disease; of the 19 cases with high MIB-1 value, five died of disease. The statistical difference between MIB-1 and prognosis was not significant. Three of the 35 (8.5%) cases were found to be positive with p53 protein; no correlation was observed between p53 immunoreactivity and prognosis. Conclusion  It appears that the MIB-1 value and p53 immunoreactivity have no relation with prognosis in pediatric medulloblastomas. However, it is convenient to support these findings with large series.     

Acute human T-lymphotropic virus type 1-associated myelopathy: a clinicopathologic study

BACKGROUND: Recently, acute human T-lymphotropic virus type 1-associated myelopathy (HAM) was reported clinically without pathologic information. We report an autopsy case of acute HAM. OBJECTIVE: To report the case of a 52-year-old man with acute-onset gait disturbance followed by rapidly progressive paraplegia, who died 9 months later. RESULTS: The postmortem study showed swelling of the thoracic spinal cord. Histologically, there was inflammation and vacuolation in the white matter. CONCLUSION: We propose that these pathologic findings, mimicking tropical spastic paraparesis, may represent the characteristic pathologic features of acute HAM.     

Truncated NF2 proteins are not detected in meningiomas and schwannomas

Neurofibromatosis type 2 is caused by mutations in the NF2 tumor suppressor gene. The NF2 gene encodes a 595‐aminoacid protein, presumably functioning as a membrane‐organizing element. Theoretically, the majority of mutations found in the NF2 gene should lead to a truncated protein product. Using immunoprecipitation with an antibody raised to N‐terminal sequences of the NF2 protein, the authors sought to demonstrate the presence of truncated NF2 proteins in tumors. From 17 of 19 tumors (14 meningiomas and five schwannomas), 12 of which have previously been shown to harbor truncating NF2 mutations, wild‐type NF2 protein was immunopreci‐pitated. From two tumors no protein was precipitated. Truncated NF2 proteins were not observed. The authors conclude that mutant NF2 proteins are unstable and undergo accelerated degradation.     

Secretory meningioma: clinicopathologic features of eight cases.

The clinical and morphological features of eight patients with meningothelial meningiomas with numerous pseudopsammoma bodies (secretory meningiomas) are presented. The six female and two male patients ranged in age from 43 to 68 years. Tumours were located at the petroclival region in two, the lateral parasellar region in two, the petrous apex in one and the sphenoid ridge in three patients. On magnetic resonance imaging, they were iso or hypointense on T1-weighted images, and hyper or isointense on T 2-weighted images. Peritumoral brain edema was absent in five cases, and was mild to moderate in three cases. Serum carcinoembryonic antigen (CEA) levels were measured preoperatively in three patients, with one having an elevated serum CEA level which re turned to normal following tumour resection. Immunohistochemical analysis on the resected tumour tissues, pseudopsammoma bodies and surrounding tumour cells were shown to be CEA-positive. Ultrastructurally, pseudopsammoma bodies were composed of granular and filamentous materials located predominantly in the intracellular lumina, which were lined by microvilli. While these morphological features of focal epithelial and secretory differentiation of tumour cells call attention to the broad spectrum of differentiation properties of meningiomas, the biological behavior of the eight tumours reported herein corresponded to those of meningiomas in general.     

Calpain‐dependent proteolysis of NF2 protein: Involvement in schwannomas and meningiomas

The neurofibromatosis type 2 (NF2) protein, known as merlin or schwannomin, is a tumor suppressor, and the NF2 gene has been found to be mutated in the majority of schwannomas and meningiomas, including both sporadically occurring and familial NF2 cases. Although the development of these tumors depends on the loss of merlin, the presence of tumors lacking detectable NF2 mutations suggests different mechanisms for inactivating merlin. Recent studies have demonstrated cleavage of merlin by calpain, a calcium‐dependent neutral cysteine protease, and marked activation of the calpain system resulting in the degradation of merlin in these tumors. Increased turnover of merlin by calpain in some schwannomas and meningiomas exemplifies tumorigenesis linked to the calpain‐mediated proteolytic pathway.     

难治性癫(癎)273例的临床病理学分析

目的 研究难治性癫(癎)的临床病理学特点.方法 对2005年1月至2007年12月在首都医科大学宣武医院接受致(癎)灶外科手术切除治疗的连续273例患者的临床及病理学资料进行回顾性分析.结果 273例患者的平均发病年龄为11.0岁,平均病程为11.2年.组织学具体分型:皮质发育畸形(MCD)158例,搬痕性脑回63例,肭肿瘤26例,中枢神经系统炎症性病变13例,血管畸形3例,囊肿3例,胆脂瘤1例,其他分类未明6例.其中MCD又包括局灶性皮质发育不良(FCD)Ⅰ型104例(平均发病年龄11.1岁,平均病程11.2年),FCDⅡ型30例(平均发病年龄7.9岁,平均病程12.7年),轻微皮质发育不良(mild MCD)6例,结节性硬化6例,多小脑回3例,其余皮质发育不良9例.158例MCD中有31例伴有海马硬化的病理学表现.134例FCD中FCD Ⅰ B型占86例(64.2%),多位于颢叶(45例).脑肿瘤26例(平均发病年龄14.5岁,平均病程6.3年),其中20例为混合性神经元-胶质肿瘤(76.9%),常见于颞叶,多数周边伴有皮质发育不良的病理学改变.结论 难治性癫(癎)中最常见的病理学类型依次分别为MCD、瘢痕性脑回和肿瘤.FCD最常见的病理学类型为FCD Ⅰ B型,多位于颞叶,常伴有海马硬化.难治性癫(癎)相关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.     

Venous congestive myelopathy: Three autopsy cases showing a variety of clinicopathologic features

We describe three patients with progressive myelopathy, in whom autopsy revealed spinal cord pathology compatible with that of venous congestive myelopathy (VCM) associated with dural arteriovenous fistula (AVF), formerly known as angiodysgenetic necrotizing myelopathy (Foix–Alajournine syndrome). In these three patients, common symptoms were gait disturbance and sensory disturbance of the extremities, and these symptoms slowly worsened. The clinical diagnoses varied and included spinal cord intramedullary tumor, cervical spondylosis and multiple sclerosis. At autopsy, all the patients showed enlarged, tortuous venous vessels on the dorsal surfaces of the spinal cord at the affected levels. In the affected spinal cord parenchyma, necrotic lesions manifested by various degrees of neuronal loss and gliosis, with increased numbers of hyalinized vessels, were evident. The presence or absence of associated spinal dural AVF could not be identified histopathologically. Even with the help of modern neurological examination methods, early and accurate clinical diagnosis of VCM is sometimes difficult. When encountering patients with progressive myelopathy, VCM, although recognized as rare, should be considered as an important differential diagnosis.     

22例无症状性脑膜瘤临床诊治

目的 探讨无症状性脑膜瘤的临床特点和治疗.方法 回顾总结1998-2006年22例无症状脑膜瘤患者的临床诊断治疗和随访资料.结果 11例手术患者肿瘤都得到全切,未出现神经功能障碍,3例行立体定向放射治疗患者随访中未发现肿瘤增生.8例随访患者观察肿瘤生长缓慢,肿瘤最大径增长不超过1cm,最长随访(33个月)患者脑膜瘤由原来2cm增生至2.8cm.无症状脑膜瘤具有以下特点:(1)老年患者居多.(2)脑膜瘤一般较小.(3)脑膜瘤多发生于大脑凸面,且远离脑脊液通路和功能区.(4)首诊症状不典型,甚至无任何症状.(5)病理类型以内皮型、砂粒型、成纤维型等生长缓慢的为多.(6)影像学检查瘤周水肿不明显.结论 若发现了无症状性脑膜瘤,并非需马上手术治疗,还要结合病人的具体情况,考虑年龄、肿瘤部位及大小、瘤周水肿等因素决定是否需手术治疗.     

NF2 gene expression in sporadic meningiomas: Relation to grades or histotypes real time‐PCR study

One of the most common regions involved in the meningiomas tumorigenesis is chromosome 22q where the NF2 gene resides. The deficiency or loss of the NF2 gene product, merlin/schwannomin, plays a role in tumor development and metastatization. Conflicting results have been reported on the prognostic value of merlin in meningiomas. Several studies have indicated NF2 gene inactivation as an early tumorigenic event unrelated to the histological grade or clinical behavior. On the contrary, the NF2 gene alteration rate differs between the different histotypes. A pathogenesis independent from the NF2 gene has been suggested in meningothelial meningiomas. In the present work, we studied the NF2 gene expression through real time‐PCR (RT‐PCR) in 30 meningiomas. The average of the NF2 gene expression of all meningiomas was considered as reference value. The average of expression of WHO grade I and II meningiomas was higher than the average of all meningiomas, whereas that of WHO grade III meningiomas was lower. When we compared the NF2 gene expression in the different meningioma grades we did not note a significant difference (P = 0.698) despite the tendency to decrease from grade I to grade III. The average expression of meningothelial meningiomas was higher than the reference value, and that of non‐meningothelial meningiomas was lower. The difference in NF2 gene expression between meningothelial and non‐meningothelial meningiomas was statistically significant (P = 0.013). Our data supports the finding that alterations in NF2 gene alteration are histotype related but not grade related.     

A study of reduction of NF 2 protein, mRNA and loss of 22 q in sporadic meningiomas]

Neurofibromatosis 2(NF 2) is one of the tumor suppressor genes, and its disorder has been reported in sporadic meningiomas. We investigated some reduction of expression of NF 2 protein and mRNA in 33 sporadic meningiomas, using immunohistochemistry and in situ hybridization, respectively. Seventeen of 33 (51.5%) meningiomas demonstrated significantly reduced or absent NF 2 protein expression. Its mRNA was also reduced or absent in 11 of 24(45.8%) meningiomas, and some statistically significant correlation was shown between reductions of NF 2 protein and its mRNA. Furthermore, we studied about loss of 22 q in 5 meningiomas with fluorescence in situ hybridization. In the cases with reduction of NF 2 protein and/or mRNA, 22 q telomere signals were observed as loss of heterozygosity. On the other hand, in the cases with expression of NF 2 protein and mRNA, 22 q telomere signals were normal. In conclusion, reduction or absence of NF 2 protein and mRNA may play an important role in the tumorigenesis of about half number of sporadic meningiomas.     

Non-familial Creutzfeldt-Jakob disease: a study of 53 cases

Creutzfeldt-Jakob disease (CJD) is the most frequent human spongiform encephalopathy. We have analyzed 53 cases of definite non familial CJD over a study period of 28 years. All were autopsied in the same neuropathological unit. Clinical and epidemiological data were in accordance with previous studies: low incidence of CJD under the age of 40, high incidence around the sixty years of age (26%) a sex ratio at 0.65 and high frequency of myoclonus, dementia and cerebellar ataxia during evolution (78%). This study highlights the rapidity at the onset of the disease (within 24 hours) in 16% of the cases. EEG disclosed typical pseudoperiodic activity in only 53% of cases and cerebral MRI showed high T2 signal intensity in basal nuclei in 15%. This regional study is the second of its nature to be carried out in France, the first one covering the area of Paris.     

Management of pediatric intracranial meningiomas: an analysis of 31 cases and review of literature

Objective

The purpose of this study is to understand the epidemiology, clinical features, behavior, and the prognostic factors that influence the outcome of intracranial meningiomas in children.

Methods

Thirty-one patients with age less than 18 years who underwent surgery for intracranial meningiomas during the period of at 1988–2012 at Voluntary Health Services Hospital, Chennai, India were studied. These formed 3.7 % of the total 831 cases of intracranial meningiomas operated at the institute.

Results

The study group included 22 (71 %) males and 9 (29 %) females. The mean age of presentation was 15 years, with the youngest being 9 months old. Two (6 %) had evidence of neurofibromatosis type 2 (NF2). The most common symptoms at presentation were seizures in 11 (35.5 %), weakness of limbs in 11 (35.5 %), and raised intracranial pressure in 10 (32 %). Convexity meningiomas were seen in 16 (51 %) and skull base in 15(49 %). Multiple meningiomas was seen in two (6 %) of the patients and intraventricular location was found in one patient (3 %). Two (6 %) had evidence of NF2. Gross total excision was achieved in 26 (83 %) and subtotal excision in 5 (17 %). WHO grade I was found in 20 (64 %) and higher grade was seen in 11 (36 %). The mean follow-up was 46.2 months. Recurrence was seen in 20 patients (64 %). In patients with higher grade or with recurrence resurgery and radiotherapy was given. Three (9 %) had multiple recurrences. On a mean follow-up of 46.2 months, 25 patients (81 %) were neurologically intact, 5 (16 %) were having moderated disability, and 1 (3 %) patient died.

Conclusions

Childhood meningiomas are uncommon lesions with a slight male predominance. They can have a varied clinical presentation. Higher grade is found more frequently compared with adults. Gross total resection is the goal and in higher grade meningiomas radiotherapy helps as a good adjuvant. Though the rate of recurrence is high, resurgery and radiotherapy gives a good outcome.