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Aminoacyl-tRNA synthetases (aaRS) are ubiquitously expressed enzymes responsible for ligating amino acids to their cognate tRNA molecules through an aminoacylation reaction. The resulting aminoacyl-tRNA is delivered to ribosome elongation factors to participate in protein synthesis. Seryl-tRNA synthetase (SARS1) is one of the cytosolic aaRSs and catalyzes serine attachment to tRNASer . SARS1 deficiency has already been associated with moderate intellectual disability, ataxia, muscle weakness, and seizure in one family. We describe here a new clinical presentation including developmental delay, central deafness, cardiomyopathy, and metabolic decompensation during fever leading to death, in a consanguineous Turkish family, with biallelic variants (c.638G>T, p.(Arg213Leu)) in SARS1. This missense variant was shown to lead to protein instability, resulting in reduced protein level and enzymatic activity. Our results describe a new clinical entity and expand the clinical and mutational spectrum of SARS1 and aaRS deficiencies.

NFATc2-rearranged sarcomas (NFATc2-Sarcomas) are infrequent round cell tumors characterized by EWSR1-NFATc2 fusions and FUS-NFATc2 fusions. Although our knowledge on these neoplasms has increased recently, novel diagnostic tools and more comprehensive series are still needed. Here, we describe the features of a series of seven molecularly confirmed NFATc2-Sarcomas (EWSR1-NFATc2, n = 4; FUS-NFATc2, n = 3) and demonstrate the utility of AGGRECAN immunohistochemistry for their identification. Patients were four males and three females, ranging in age from 19 to 66 years (median: 33). All were primary bone tumors (femur, n = 4; tibia, n = 2; ilium, n = 1), frequently infiltrating the surrounding soft tissues. Treatment often consisted of neoadjuvant chemotherapy and surgery. Follow-up was available for six patients (median 18 months, range 5-102 months), three patients died of disease and four patients are currently alive. Histologically, tumors consisted of monotonous round cells growing in lobules and sheets in variable amounts of fibrous to myxoid stroma. Other findings included spindle cells, corded and trabecular architecture, nuclear pleomorphism, cartilaginous differentiation, and osteoid-like matrix. Histological response to neoadjuvant chemotherapy was poor in all resection specimens available for review (n = 4). Tumors were diffusely positive for AGGRECAN and CD99 (7/7), and a subset expressed Pan-Keratin (AE1-AE3; 3/6), S100 (2/6), BCOR (2/6), ETV-4 (2/5), WT1 (2/6), and ERG (2/5). Desmin, NKX3-1, and SATB2 were negative (0/6). Diffuse AGGRECAN staining was also seen in 8/129 round cell sarcomas used for comparison, including mesenchymal chondrosarcoma (7/26) and CIC-sarcoma (1/26). Array-CGH showed complex karyotypes with recurrent deletions of tumor suppressor genes (CDKN2A/B, TUSC7, and DMD) in three FUS-NFATC2 cases and a simpler profile without homozygous losses in one EWSR1-NFATc2 case. Segmental chromosomal gains covering the loci of the fusion genes were detected in both variants. Overall, our study confirms and expands previous observations on NFATc2-sarcomas and supports that AGGRECAN is a useful biomarker of these tumors.

Background Tumors arising from oculomotor nerve are rare, with few cases reported in the literature. Generally, whereas schwannomas are well encapsulated tumors, neurofibromas tend to invade the entire nerve fibers. These differences influence surgical resection and neurological clinical outcome, with neurofibroma often requiring the sacrifice of the nerve. Accordingly, an incorrect preoperative diagnosis can lead to incomplete patient counseling before surgery. Case Description We report 2 cases: a patient with oculomotor schwannoma and a patient with oculomotor neurofibroma. After tumor resection, the patient with a diagnosis of schwannoma recovered with 3rd nerve palsy, while patient with the neurofibroma developed a complete oculomotor nerve deficit. For each patient, surgical strategy and neurological outcome are elucidated in relation with differences in preoperative magnetic resonance imaging and histology. Conclusions To the best of our knowledge, this is the first report of an oculomotor neurofibroma. When an oculomotor nerve tumor is suspected, a careful preoperative evaluation of magnetic resonance imaging guides in distinguishing the different histology, in selecting the treatment strategy, and in correctly informing the patient on expected postoperative neurologic outcome.

The diagnosis of anaplastic meningioma (AM) (WHO grade III) is based on the presence of a high mitotic index (MI) and/or overt anaplasia. Only few data exist about the reproducibility and prognostic value of overt anaplasia. Additionally, the prognostic value of H3K27me3 loss in AM has not yet been demonstrated. Our objectives were to evaluate the reproducibility and prognostic value of WHO criteria and H3K27me3 loss in a multicenter series of 66 AM. Interobserver reproducibility was good for the determination of WHO grade (Kappa = 0.671) and MI (intraclass correlation coefficient [ICC] = 0.649), and fair for assessment of overt anaplasia (Kappa = 0.366). Patients with meningiomas showing high MI had significantly shorter overall survival (OS) than patients with meningiomas showing overt anaplasia without high MI (p = 0.009). OS was significantly lower in case of overt anaplasia with low MI (

Langerhans cell histiocytosis (LCH) is a rare condition affecting children more frequently than adults. LCH can involve any organ in the body and has a wide spectrum of clinical presentation from a single self-healing bone lesion to a multisystemic life-threatening disease. The diagnosis of LCH requires histology with compatible clinical and radiological findings. Positive immunochemistry for both CD1a and CD207 is required for a definitive diagnosis of LCH. The majority of LCH shares oncogenic BRAFV600E mutation. We report the case of a 55-year-old adult who presented with a single lytic self-healing lesion of the skull, invading adjacent soft tissues. The histology and cytology were also typical of LCH, and tumor cells contained the BRAFV600E mutation. However, histiocytes were negative for CD1a and CD207. We suggest that this case might be considered as LCH, despite its abnormal phenotype. .

Background Considering that pediatric high-grade gliomas (HGGs) are biologically distinct from their adult counterparts, the objective of this study was to define the landscape of HGGs in adolescents and young adults (AYAs). Methods We performed a multicentric retrospective study of 112 AYAs from adult and pediatric Ile-de-France neurosurgical units, treated between 1998 and 2013 to analyze their clinicoradiological and histomolecular profiles. The inclusion criteria were age between 15 and 25 years, histopathological HGG diagnosis, available clinical data, and preoperative and follow-up MRI. MRI and tumoral samples were centrally reviewed. Immunohistochemistry and complementary molecular techniques such as targeted/next-generation sequencing, whole exome sequencing, and DNA-methylation analyses were performed to achieve an integrated diagnosis according to the 2016 World Health Organization (WHO) classification. Results Based on 80 documented AYA patients, HGGs constitute heterogeneous clinicopathological and molecular groups, with a predominant representation of pediatric subtypes (histone H3-mutants, 40%) but also adult subtypes (isocitrate dehydrogenase [IDH] mutants, 28%) characterized by the rarity of oligodendrogliomas, IDH mutants, and 1p/19q codeletion and the relative high frequency of “rare adult IDH mutations” (20%). H3G34-mutants (14%) represent the most specific subgroup in AYAs. In the H3K27-mutant subgroup, non-brainstem diffuse midline gliomas are more frequent (66.7%) than diffuse intrinsic pontine gliomas (23.8%), contrary to what is observed in children. We found that WHO grade has no prognostic value, but molecular subgrouping has major prognostic importance. Conclusions HGGs in AYAs could benefit from a specific classification, driven by molecular subtyping rather than age group. Collaborative efforts are needed from pediatric and adult neuro-oncology teams to improve the management of HGGs in AYAs.

International audience; ObjectiveThe great heterogeneity of meningiomas is challenging and we need to distinguish relevant subgroups. Spheno-orbital osteomeningiomas (SOOM) constitute a clinically specific entity, with slow-growing benign osteo-meningiomatous tumors, which recur after surgery in one fourth of cases. Neurosurgical daily practice, supported by the literature, shows that the vast majority of patients with SOOM are women, and we explored whether their epidemiological and hormonal profiles suggest a progesterone influence.MethodsWe retrospectively documented all radiologically and histologically confirmed cases of SOOM operated in 2005–2019 in our institution. We completed the clinical and hormone history by systematic telephone interviews.ResultsIn the literature, SOOM occur significantly more often in women than other meningiomas (749/847, 86.4% versus 73.8%, p = 0.002). Among 175 cases, we included 124 patients, 93.5% were women, younger than men (51 ± 5 versus 63 ± 8, p = 0.02). Women’ meningiomas showed more progesterone receptors (96.4% versus 50%, p

Background Medulloblastomas may occur in a predisposition context, including familial adenomatosis polyposis. Medulloblastomas related to a germline pathogenic variant of adenomatous polyposis coli (APC) remain rare and poorly described. Their similarities with sporadic WNT medulloblastomas still require description. Methods We performed a multicentric retrospective review of 12 patients treated between 1988 and 2018 for medulloblastoma with an identified or highly suspected (personal or familial history) APC germline pathogenic variant. We report personal and familial history APC gene pathogenic variants whenever available: clinical and histologic characteristics of the medulloblastoma, treatments, and long-term outcome, including second tumor and late sequelae. Results Medulloblastomas associated with APC pathogenic variants are mainly classic (11/11 patients, 1 not available), nonmetastatic (10/12 patients) medulloblastomas, with nuclear immunoreactivity for ß-catenin (9/9 tested cases). Ten of 11 assessable patients are disease free with a median follow-up of 10.7 years (range, 1–28 y). Secondary tumors included desmoid tumors in 7 patients (9 tumors), 1 thyroid carcinoma, 2 pilomatricomas, 1 osteoma, 1 vertebral hemangioma, and 1 malignant triton in the radiation field, which caused the only cancer-related death in our series. Conclusions Medulloblastomas associated with an APC pathogenic variant have an overall favorable outcome, even for metastatic tumors. Yet, long-term survival is clouded by second tumor occurrence; treatment may play some role in some of these second malignancies. Our findings raise the question of applying a de-escalation therapeutic protocol to treat patients with APC germline pathogenic variants given the excellent outcome, and reduced intensity of craniospinal irradiation may be further evaluated.

Pediatric chordomas are rare malignant neoplasms, and few data are available for optimizing therapeutic strategies and outcome. This study aimed at evaluating how best to manage them and to identify prognostic factors. This multicentric retrospective study included 40 children diagnosed with chordomas between 1966 and 2012. Clinical, radiological, and histopathological data, treatment modalities, and outcomes were reviewed. The median age was 12 years old. Most chordomas were histologically classical forms (45.5%) and were mostly located at the skull base (72.5%). The overall survival (OS) was 66.6% and 58.6%, and progression-free survival (PFS) was 55.7% and 52% at 5 and 10 years, respectively. Total resection was correlated with a better outcome (p = 0.04 for OS and PFS, log-rank). A histopathological/immunohistochemical grading system recently crafted for adults was applied. In a multivariate analysis, it significantly correlated with outcome (PFS and OS, p = 0.004), and the loss of BAF47 immunoexpression appeared to be a significant independent prognostic factor (PFS, p = 0.033). We also identified clinical and histopathological parameters that correlated with prognosis. A new grading system combined with the quality of surgical resection could help classify patients to postpone radiotherapy in case of low risk. Targeted therapy and reirradiation at recurrence may be considered as potential therapeutic strategies.

The long-term use of cyproterone acetate (CPA) is associated with an increased risk of developing intracranial meningiomas. CPA discontinuation most often induces a stabilization or regression of the tumor. The underlying biological mechanisms as well as the reasons why some meningiomas still grow after CPA discontinuation remain unknown. We reported a series of patients presenting CPA-induced meningiomatosis with opposed tumor evolutions following CPA discontinuation, highlighting the underlying histological and genetic features. Patients presenting several meningiomas with opposite tumor evolution (coexistence of growing and shrinking tumors) following CPA discontinuation were identified. Clinical and radiological data were reviewed. A retrospective volumetric analysis of the meningiomas was performed. All the growing meningiomas were operated. Each operated tumor was characterized by histological and genetic analyses. Four women with multiple meningiomas and opposite tumor volume evolutions after CPA discontinuation were identified. Histopathological analysis characterized the convexity and tentorial tumors which continued to grow after CPA discontinuation as fibroblastic meningiomas. The decreasing skull base tumor was characterized as a fibroblastic meningioma with increased fibrosis and a widespread collagen formation. The two growing skull base meningiomas were identified as meningothelial and transitional meningiomas. The molecular characterization found two NF2 mutations among the growing meningiomas and a PIK3CA mutation in the skull base tumor which decreased. To our knowledge, this is the first report describing an atypical tumor evolution of CPA-associated meningiomas after CPA discontinuation. The underlying biological mechanisms explaining this observation and especially the close relationship between mutational landscapes and embryologic origins of the meninges in CPA-related meningiomas as well as their clonal origin require further research.

Objective:To assess the characteristics and outcomes of patients with AIDS-related primary CNS lymphoma (AR-PCNSL) in the combined antiretroviral therapy (cART) era systematically treated with high-dose methotrexate (HD-MTX).Methods:We retrospectively analyzed (intention-to-treat analysis) 51 consecutive patients with AR-PCNSL (median age 39 years) who were diagnosed from 1996 to 2014 and treated with a median of 6 (range 1–15) infusions of HD-MTX (3 g/m2) combined with cART.Results:Median all-patients' and survivors' follow-up lasted 23 (range 0–186) and 76 (range 23–186) months, respectively. At PCNSL diagnosis, 83% of the patients were on cART, median plasma HIV load was 175,600 copies/mL, and median CD4+ T-cell count was 24/μL. Median Eastern Cooperative Oncology Group performance status was 2 (range 1–4). Median overall survival (OS) was 5.7 years, with 5- and 10-year rates of 48% and 41%. Median time to progression was not reached (69% at 10 months). PCNSL was the direct cause of 14 deaths, all observed within the 10 months after its diagnosis: 6 patients died before HD-MTX could be administered, 4 had refractory disease, and 4 relapsed. Multivariate analyses retained time interval between AIDS diagnosis and PCNSL diagnosis, age at AR-PCNSL diagnosis, and deep brain structure involvement as independent OS-predictive factors. To restore effective immune function, cART tailored to HIV genotypes was started and combined with HD-MTX; no interactions and no immune reconstitution inflammatory syndrome occurred. No patient died of acute treatment-related toxicity, and 21 of 51 (41%) patients experienced grade 3/4 toxicity.Conclusions:Combined short-term HD-MTX monochemotherapy and optimal cART simply and effectively treat AR-PCNSL, achieving long-term survival with few relapses.Classification of evidence:This study provides Class IV evidence that short-term HD-MTX monochemotherapy improves long-term survival of patients with AIDS with primary CNS lymphoma receiving cARTs.

Objective To explore potential spreading to peripheral nerves of the mitochondrial dysfunction in chronic progressive external ophthalmoplegia (CPEO) by assessing axonal excitability. Methods CPEO patients (n = 13) with large size deletion of mitochondrial DNA and matching healthy controls (n = 22) were included in a case-control study. Muscle strength was quantified using MRC sum-score and used to define two groups of patients: CPEO-weak and CPEO-normal (normal strength). Nerve excitability properties of median motor axons were assessed with the TROND protocol and changes interpreted with the aid of a model. Results Alterations of nerve excitability strongly correlated with scores of muscle strength. CPEO-weak displayed abnormal nerve excitability compared to CPEO-normal and healthy controls, with increased superexcitability and responses to hyperpolarizing current. Modeling indicated that the CPEO-weak recordings were best explained by an increase in the ‘Barrett-Barrett’ conductance across the myelin sheath. Conclusion CPEO patients with skeletal weakness presented sub-clinical nerve excitability changes, which were not consistent with axonal membrane depolarization, but suggested Schwann cell involvement. Significance This study provides new insights into the spreading of large size deletion of mitochondrial DNA to Schwann cells in CPEO patients.

Clear cell meningioma (CCM) is a rare grade II histopathological subtype that usually occurs in young patients and displays high recurrence rate. Germline SMARCE1 mutations have been described in hereditary forms of this disease and more recently in small syndromic and sporadic CCM series. The diagnostic value of SMARCE1 in distinguishing between CCM and other meningioma variants has not been yet established. The aim of our study was to investigate the status of SMARCE1 in a series of CCMs and its morphological mimickers. We compared the performance of an anti-SMARCE1 antibody and the molecular analysis of the SMARCE1 gene in a retrospective multicenter series of CCMs. All CCMs lossed SMARCE1 immunoexpression. Bi-allelic inactivating events were found by NGS-based sequencing in all of these cases, except for one, which was incompletely explored, but had a wild-type sequence. We then validated the anti-SMARCE1 antibody specificity by analyzing additional 305 pediatric and adult meningiomas of various subtypes and 15 non-meningioma clear cell tumors by SMARCE1 immunohistochemistry. A nuclear immunostaining was preserved in all other meningioma variants, as well as non-meningioma clear cell tumors. In conclusion, our series showed, for the first time, that SMARCE1 immunostaining is a highly sensitive biomarker for CCM, useful as a routine diagnostic biomarker.

We report the case of a 63-year-old healthy patient who was admitted for surgery of a suprasellar tumor with extension to the optic chiasm responsible of visual disturbance. Histopathological examination revealed a tumoral proliferation composed of epithelioid cells without atypia arranged in cords in a mucinous matrix surrounded by some lymphocytic inflammatory infiltrates. On immunohistochemistry, the neoplastic cells strongly expressed GFAP and CD34, a weak expression of EMA, an expression of TTF1 without immunoreactivity for brachyury. Ki-67 labeling index was low around 1%. The diagnosis of chordoid glioma was made. Surprisingly, tumor cells expressed IDH1R132H but molecular analysis did not reveal any mutation of IDH1/2 genes. There was no expression of p53 but high overexpression of EGFR. Chordoid glioma is a rare and low-grade entity. The precise histogenesis remains debated. Our case is unusual because of the infiltration of the optic chiasm and because of the immunoexpression of IDH1R132H without underlying mutations of IDH1/2 genes.

Subependymal giant-cell astrocytomas (SEGAs) are low grade intraventricular tumors typically found in patients with tuberous sclerosis complex (TSC). The occurrence of SEGA in non TSC patients is very rare and from a genetic point of view these so-called solitary SEGA are thought to result either from somatic mutations in one of the TSC genes (TSC1 or TSC2) limited to the tumor, or be part of a “forme fruste” of TSC with somatic mosaicism. We report on three new cases of solitary SEGA with germline and somatic mutation analysis. We retrospectively analyzed TSC genes in three patients with a solitary SEGA using next-generation sequencing technique. In the three patients, a somatic mutation of TSC1 or TSC2 was found only in the tumor cells: one patient had a TSC1 heterozygote mutation, involving the natural acceptor splicing site of intron 15 (c.1998-1G > A (p.?). Two patients had a TSC2 mutation located in the canonical splicing donor site of intron 5 (c.599 + 1G > A) in 70% of the alleles in one patient and in exon 9: c.949_955dup7 (p.V319DfxX21) in 25 of the alleles in the second patient. No other TSC mutations were found in patient’s blood or tumor and those identified mutations were absent in blood DNA from parents and siblings. We therefore conclude that solitary SEGA can occur with a TSC1 or TSC2 mutation limited to the tumor in patients without TSC.

We report the case of a 30-year-old woman with histologically proven monostotic fibrous dysplasia of C2 revealed by a pathological fracture of the odontoid process. Radiological investigations showed a ground-glass mineralization of the vertebral body, a centimetric lytic area with poorly defined margins involving the inferior part of the vertebral body and inferior endplate and a fracture through an osteolytic area in the base of the odontoid process. Owing to the vertebral instability, a surgical procedure combining C0–C5 fixation and posterior bone grafting was performed. The surgical biopsy was inconclusive and pathological confirmation was finally obtained through a percutaneous needle biopsy under fluoroscopic guidance. At 26-month follow-up, the patient still experienced mild persistent cervical posterior neck pain and stiffness possibly related to a C5–6 laxity below the intervertebral fixation. This case combines three radiological findings, which are unusual in fibrous dysplasia: monostotic presentation involving the spine, some aggressive radiographic features, and a pathological fracture.

Intracranial germinomas (IGs) are rare malignant germ cell tumors. The septum pellucidum (SP) is an extremely rare site of IGs. To our knowledge we report the first patient presenting with synchronous involvement of the SP and the sellar region. A 28-year-old woman presented with unsteady gait, mild left motor deficit, polydipsia and polyuria of 2-month duration. Imaging revealed a multicystic butterfly lesion in the SP extending to the frontal lobes, with unusual CT and MRI features, associated with a sellar area lesion. A navigation-guided biopsy revealed a pure germinoma. MRI at 12 months after the completion of the radiation therapy showed the resolution of the lesions. She achieved complete remission at 8-year follow-up. IG arising in the SP is rare but should be considered in the differential diagnosis, especially in young adult and particularly in male, presenting with multi-cystic lesion. The presence of a synchronous mass is a clue for the presumptive diagnosis of germinoma. These findings suggest that IG in SP may present as a large tumor with large cysts and may look as central neurocytoma. ADC value is helpful to differentiate them., Highlights • The Septum Pellucidum is an exceptional localization of Germ Cell Tumors. • Synchronous Septum Pellucidum and sellar region Germinoma has been never reported. • Septum Pellucidum Germinoma can mimic Central Neurocytoma. • Apparent diffusion coefficient may help to achieve accurate diagnosis. • A synchronous lesion in the sellar region is a clue for the presumptive diagnosis.

International audience; Cerebral amyloid angiopathy related inflammation (CAA-RI) is a rare form of CAA characterized by subacute encephalitic symptoms (cognitive decline, seizures, focal deficits) associated with extensive and confluent white matter lesions co-localizing with lobar microbleeds on brain MRI. We report two cases of unusual CAA-RI mimicking meningoencephalitis but without typical brain lesions on FLAIR and T2* sequences. These 2 cases may extend the clinical spectrum of CAA-RI by suggesting the possible occurrence of quite purely meningeal forms of CAA-RI.

The sellar region is a tiny anatomic compartment in which many lesions and developmental diseases can be found. If pituitary adenomas represent most of the sellar mass, it is important to recognize other pathologic conditions before any surgical procedure, because the optimal treatment may differ considerably from one lesion to another. A careful clinical evaluation followed by neuroimaging studies and an endocrinologic and ophtalmologic workup will lead, in most cases, to a diagnosis with near certainty. This article provides an overview of sellar diseases with emphasis on their most useful characteristics for clinical practice.

Cryptococcosis is a serious infection, possibly lethal, of worldwide distribution. It mainly affects immunosuppressed patients resulting with pulmonary and/or meningeal involvements or disseminated infections. Due to the rarity of visceral and osseous infections, and to the absence of specific clinical symptoms, this diagnosis is often deferred. Resulting of diagnostic errors, samples are often directed to the department of pathology and more rarely to the department of mycology. Histopathological examination appears crucial, highlighting encapsulated yeasts with alcian blue staining. Once the diagnosis is performed, an appropriate antifungal therapy must be quickly introduced because these infections are associated with a high mortality rate. The aim of our work was to report five extra-cerebral and extra-pulmonary cryptococcosis cases, to describe their histopathological features, to evoke diagnostic techniques and to discuss the differential diagnoses.

Vertebral hemangiomas are relatively frequent among tumors of the spine. Most of them are asymptomatic and the diagnosis is usually made based solely on imaging. However, although rare, some hemangiomas with atypical imaging features (aggressive hemangiomas) can pose a diagnostic challenge. Clinically, these patients present with neurological symptoms. In imaging, aggressive hemangiomas appear as lesions with significant osseous expansion or extraosseous extension, mimicking the appearance of other tumors, such as metastasis or plasmacytoma. In such cases, a biopsy is often required to obtain a histopathological diagnosis in order to rule out the differential diagnoses mentioned above. We report on two cases of aggressive hemangiomas whose diagnosis remained uncertain until the pathology analysis. On CT-scan control immediately after biopsy, we have been surprised to observe the formation of gas bubbles inside the biopsied lesion, spreading over almost the whole vertebra. This gas web sign may support its liquid-filled spaces composition and its benign nature. Our goal was to highlight this finding and its usefulness.

Numerous molecular alterations have been described in supratentorial high-grade gliomas (1p19q co-deletion, IDH1/2, histone H3, hTERT promotor mutations, loss of ATRX) which have led to a new histomolecular classification of diffuse gliomas. We aimed at describing these alterations in a series of 19 adults with pure cerebellar high-grade gliomas. Systematic immunohistochemical analyses, including that of IDH1R132H, ATRX, p53, PTEN, EGFR, p16, FGFR3, BRAFV600E, mismatch repair proteins, H3K27me3, H3K36me3, and H3K27M; molecular analyses of IDH1/2, hTERT, BRAF, H3F3A, and HIST1H3B mutation hotspots; and EGFR, PTEN FISH were retrospectively performed in a multicentric study. We histopathologically identified 14 glioblastomas, 4 grade III astrocytomas and 1 gliosarcoma. Two cases showed a H3F3A K27M mutation. Only one case harbored a classical profile of glioblastoma with hTERT mutation, EGFR gain and 10q loss. The most frequent alteration was the absence of p16 immunoexpression. We report a histomolecular analysis of pure cerebellar high grade gliomas. The histomolecular profile appears to be different from that of supratentorial gliomas, with no IDH1/2 gene mutations and only 1 case with a classic profile of de novo glioblastoma. In 2 cases, we identified H3F3A K27M mutation, classically described in pediatric midline gliomas. .

International audience; Background: Primary central nervous system lymphoma (PCNSL) represents a particular entity within non-Hodgkin lymphomas and is associated with poor outcome. The present study addresses the potential clinical relevance of chimeric transcripts in PCNSL discovered by using RNA sequencing (RNA-seq).Methods: Seventy-two immunocompetent and newly diagnosed PCNSL cases were included in the present study. Among them, 6 were analyzed by RNA-seq to detect new potential fusion transcripts. We confirmed the results in the remaining 66 PCNSL. The gene fusion was validated by fluorescence in situ hybridization (FISH) using formalin-fixed paraffin-embedded (FFPE) samples. We assessed the biological and clinical impact of one new gene fusion.Results: We identified a novel recurrent gene fusion, E26 transformation-specific translocation variant 6-immunoglobulin heavy chain (ETV6-IgH). Overall, ETV6-IgH was found in 13 out of 72 PCNSL (18%). No fusion conserved an intact functional domain of ETV6, and ETV6 was significantly underexpressed at gene level, suggesting an ETV6 haploinsufficiency mechanism. The presence of the gene fusion was also validated by FISH in FFPE samples. Finally, PCNSL samples harboring ETV6-IgH showed a better prognosis in multivariate analysis, P = 0.03, hazard ratio = 0.33, 95% CI = 0.12-0.88. The overall survival at 5 years was 69% for PCNSL harboring ETV6-IgH versus 29% for samples without this gene fusion.Conclusions: ETV6-IgH is a new potential surrogate marker of PCNSL with favorable prognosis with ETV6 haploinsufficiency as a possible mechanism. The potential clinical impact of ETV6-IgH should be validated in larger prospective studies.

We present a case of 27-year-old female who presented for a progressive frontal swelling with ipsilateral headache. Subsequent CT scan revealed an extradural and expansile multiloculated mass with thin and strongly enhanced septations and MRI evaluation showed internal hyperintensity on T2 with no restriction of diffusion and confirmed the multiple cystic spaces with enhancing septations and rare hemorrhagic fluid-fluid levels. Surgery was performed and diagnosis of aneurysmal bone cyst was made on frozen section. Identification of USP6 fusion gene by in situ hybridization technique permitted to confirm the diagnosis of primary ABC. Although aneurysmal bone cyst (ABC) of the skull is a very rare entity and accounts for 2-6% of all ABCs, we should think about it in front of osteolytic and cystic skull changes even with very few fluid-fluid levels. Following description of our case and differential diagnoses, we conduct a literature review of skull ABCs imaging characteristics and discuss the interest of USP6 rearrangement identification.

Medulloblastoma may occur in a context of APC germline mutation and familial adenomatous polyposis. We aimed to describe clinical features of patients with medulloblastoma occurring in this context. We performed a multicentric retrospective review of French and Belgian patients treated for medulloblastoma with identified or highly suspected (personal or familial history) APC germline mutation. Genetic status, clinical and histological characteristics, treatments and outcome were reported. Eleven patients with known or suspected APC germline mutation, mostly on exon 15 (N=6/9 available data), were diagnosed with medulloblastoma at a median age of 10.6 years [6-32]. Medulloblastomas were mainly non-metastatic (N=9/11), classic (N=9/9 available data, central review ongoing), with no significant residual tumor after surgery (N=9/11). All patients underwent radiotherapy (median craniospinal dose: 35 Gy), combined with chemotherapy for 10 patients. No relapse was noticed (median follow-up: 11 years). Secondary tumors (N=8) occurred in 7 patients, including 1 lethal malignant Triton tumor in the irradiation field, 1 thyroid carcinoma, and 6 desmoid tumors (5 abdominal tumors, 1 occipital tumor in the irradiation field). Pre-symptomatic polyposis was diagnosed for 9 patients at a median age of 15.5 years, prior to medulloblastoma for 2 of them. Medulloblastomas associated with APC germline mutation have favorable clinical outcome, even for metastatic tumors, with no relapse in this small series of patients, in line with WNT-medulloblastomas’ profile. Yet, long-term survival is clouded by second tumor occurrence, with potential radiation-induced tumors. These findings raise the question of applying de-escalation therapeutic protocol for these patients with reduced intensity craniospinal irradiation.

Osteoporosis circumscripta is sometimes observed at the skull vault and corresponds to the initial stage of Paget's disease of the bone. Differentiating osteoporosis circumscripta from other reasons for osteolytic images of the vault may be difficult. We report a case of osteoporosis circumscripta of the frontal bone. A lucent rim seen on CT scan, which was enhanced on gadolinium-enhanced MRI, delineated the abnormal bone. The patient was a 50-year-old woman who had CT scans of the skull for chronic sinusitis. Pathology examination showed typical bone changes of Paget's disease. The lucent and enhancing rim sign may help in differentiating Paget's disease from other conditions.

Aims Hypophysitis is a rare chronic inflammation of the pituitary gland corresponding currently to six histopathological subtypes. Among them, immunoglobulin- G4-related hypophysitis was recently added in this classification. The aim of this study was to perform a retrospective histopathological and immunohistochemical analysis to evaluate the prevalence of IgG4-related hypophysitis and review reported cases. Methods All samples of hypophysitis from Lariboisiere hospital were reviewed by two pathologists to assess their subtypes. An immunohistochemistry against IgG4 and IgG was performed. Slides were numerized, and IgG4-positive plasma cells and IgG plasma cells were counted in three high-power fields to evaluate the ratio. Results Eight cases were included: 5 lymphocytic hypophysitis, 1 granulomatous subtype, and 2 IgG4-related hypophysitis, affecting two young women without other coaffected organ. Conclusion Our results show that IgG4-related hypophysitis is not an exceptional entity. Storiform fibrosis and obliterative phlebitis, histopathological characteristics of IgG4-related disease in other organs, are lacking in pituitary lesions. This study proves the interest of immunohistochemistry for diagnosis of IgG4-related hypophysitis. Due to the sensibility of IgG4-disease to steroids in other organs, this finding could be of clinical relevance.

Neuropathy is the most common complication of the peripheral nervous system during the progression of diabetes. The pathophysiology is unclear but may involve microangiopathy, reduced endoneurial blood flow, and tissue ischemia. We used a mouse model of type 1 diabetes to study parallel alterations of nerves and microvessels following tissue ischemia. We designed an easily reproducible model of ischemic neuropathy induced by irreversible ligation of the femoral artery. We studied the evolution of behavioral function, epineurial and endoneurial vessel impairment, and large nerve myelinated fiber as well as small cutaneous unmyelinated fiber impairment for 1 month following the onset of ischemia. We observed a more severe hindlimb dysfunction and delayed recovery in diabetic animals. This was associated with reduced density of large arteries in the hindlimb and reduced sciatic nerve epineurial blood flow. A reduction in sciatic nerve endoneurial capillary density was also observed, associated with a reduction in small unmyelinated epidermal fiber number and large myelinated sciatic nerve fiber dysfunction. Moreover, vascular recovery was delayed, and nerve dysfunction was still present in diabetic animals at day 28. This easily reproducible model provides clear insight into the evolution over time of the impact of ischemia on nerve and microvessel homeostasis in the setting of diabetes. © 2015 Wiley Periodicals, Inc.

We report the case of an 11-year-old girl, who was admitted for surgery of an epilepsy-associated brain tumor. The radiological and clinical hypothesis was dysembryoplasic neuroepithelial tumor. Histopathological examination revealed a tumoral proliferation composed of spindle-shaped cells with palisade arrangements around vessels. Tumor cells have small, round and regular nuclei without atypia or mitosis. On immunohistochemistry, the neoplastic cells strongly expressed GFAP and showed a characteristic cytoplasmic dot-like staining with EMA (epithelial membrane antigen). Ki-67 labeling index was low. Molecular analysis failed to reveal the V600E mutation of BRAF gene. The patient was free of seizures after surgery. Angiocentric glioma is a rare brain tumor occuring preferably in children and young adults and is associated with seizures. The precise histogenesis remains debated. The treatment of choice is total resection. The prognosis is favorable if totally resected.

Erdheim-Chester disease is rare form of non-Langerhans cell histiocytosis characterized by organ infiltration of CD68+ CD1a− histiocytes. Between 500 and 600 cases have been reported. It is a multifaceted disease ranging from a solely asymptomatic bone to a fatal multisystem pattern. Bone involvement occurs in more than 90% of cases. Although not life-threatening, bone localizations can be responsible of difficult-to-treat pain and disability. Treatment depends on lesion severity. Bisphosphonates have been reported to be efficient and safe in bone involvement. We report a case of a biopsy proven bone Erdheim-Chester disease in a 65-year-old woman with history of breast cancer. Her pain was relieved after 3 perfusions of zoledronic acid and the efficiency remained at one year of follow-up.

Little is known about the genomic basis of primary central nervous system lymphoma (PCNSL) tumorigenesis. To investigate the mutational profile of PCNSL, we analyzed nine paired tumor and germline DNA samples from PCNSL patients by high throughput exome sequencing. Eight genes of interest have been further investigated by focused resequencing in 28 additional PCNSL tumors to better estimate their incidence. Our study identified recurrent somatic mutations in 37 genes, some involved in key signaling pathways such as NFKB, B cell differentiation and cell cycle control. Focused resequencing in the larger cohort revealed high mutation rates for genes already described as mutated in PCNSL such as MYD88 (38%), CD79B (30%), PIM1 (22%) and TBL1XR1 (19%) and for genes not previously reported to be involved in PCNSL tumorigenesis such as ETV6 (16%), IRF4 (14%), IRF2BP2 (11%) and EBF1 (11%). Of note, only 3 somatically acquired SNVs were annotated in the COSMIC database. Our results demonstrate a high genetic heterogeneity of PCNSL and mutational pattern similarities with extracerebral diffuse large B cell lymphomas, particularly of the activated B-cell (ABC) subtype, suggesting shared underlying biological mechanisms. The present study provides new insights into the mutational profile of PCNSL and potential targets for therapeutic strategies.

Le syndrome de Sturge-Weber est un syndrome neurocutane congenital rare associant un angiome facial dans le territoire de la premiere branche du nerf trijumeau, une atteinte de la vascularisation ophtalmique ipsilaterale et un angiome leptomeninge ipsilateral pouvant etre responsable d’une epilepsie pharmaco-resistante dans pres de 60 % des cas et d’un retard des acquisitions. Une prise en charge chirurgicale doit etre envisagee precocement chez l’enfant en terme de controle de cette epilepsie mais egalement afin de preserver au mieux le devenir cognitif. Le bilan prechirurgical permettra de proposer ou non une procedure chirurgicale en fonction de l’analyse des donnees cliniques, radiologiques et electrophysiologiques. Deux types de procedures chirurgicales peuvent etre proposees : la resection de l’angiome associee a une resection corticale dans le cas des lesions focales et la deconnexion hemispherique dans le cas des angiomes d’extension hemispherique.

BACKGROUND: The aim of this study was to correlate MRI features and molecular characteristics in anaplastic oligodendrogliomas (AOs). METHODS: The MRI characteristics of 50 AO patients enrolled in the French national network for high-grade oligodendroglial tumors were analyzed. The genomic profiles and IDH mutational statuses were assessed using high-resolution single-nucleotide polymorphism arrays and direct sequencing, respectively. The gene expression profiles of 25 1p/19q-codeleted AOs were studied on Affymetrix expression arrays. RESULTS: Most of the cases were frontal lobe contrast-enhanced tumors (52%), but the radiological presentations of these cases were heterogeneous, ranging from low-grade glioma-like aspects (26%) to glioblastoma-like aspects (22%). The 1p/19q codeletion (n = 39) was associated with locations in the frontal lobe (P = .001), with heterogeneous intratumoral signal intensities (P = .003) and with no or nonmeasurable contrast enhancements (P = .01). The IDH wild-type AOs (n = 7) more frequently displayed ringlike contrast enhancements (P = .03) and were more frequently located outside of the frontal lobe (P = .01). However, no specific imaging pattern could be identified for the 1p/19q-codeleted AO or the IDH-mutated AO. Within the 1p/19q-codeleted AO, the contrast enhancement was associated with larger tumor volumes (P = .001), chromosome 9p loss and CDKN2A loss (P = .006), genomic instability (P = .03), and angiogenesis-related gene expression (P < .001), particularly for vascular endothelial growth factor A and angiopoietin 2. CONCLUSION: In AOs, the 1p/19q codeletion and the IDH mutation are associated with preferential (but not with specific) imaging characteristics. Within 1p/19q-codeleted AO, imaging heterogeneity is related to additional molecular alterations, especially chromosome 9p loss, which is associated with contrast enhancement and larger tumor volume.

A 72-year-old man presented with a gradual bilateral decrease in visual acuity. Imaging showed lesion in the sella turcica diagnosed as meningioma but proving secondarily to be a hemangioblastoma. His neurosurgical history included a resection of a cerebellar hemangioblastoma 30 years ago. To our knowledge, such a hemangioblastoma second localization from the infratentorial to supratentorial has not been reported in the literature for patients not presenting with von Hippel–Lindau disease.

We report the neuropathological findings in 10 HIV-infected patients treated by combination antiretroviral therapy who developed subacute encephalopathy of rapidly progressive onset. Brain biopsy showed encephalitic lesions variably associated with myelin loss and slight axonal damage. There was inconstant, weak expression of HIV protein p24; tests for other pathogens were negative. The most striking feature was diffuse, perivascular and intraparenchymal infiltration by CD8+ T-lymphocytes. Six patients improved after the treatment. Four had an unfavorable outcome and died within a year. Post-mortem in one case confirmed HIV leukoencephalitis with p24-positive multinucleated giant cells, associated with acute demyelinating encephalomyelitis (ADEM) in the cerebellum. There was diffuse infiltration by CD8+ lymphocytes; CD4+ cells were virtually absent. These cases may represent a specific clinicopathological entity, of which a few comparable cases have been already described. They can be included in the wide framework of immune reconstitution disease. Such syndromes have been described with opportunistic infections, but only seldom with HIV infection of the central nervous system (CNS). Our findings support the hypothesis that CD8+ cytotoxic lymphocytes can be harmful in immune reconstitution disease, particularly in the absence of CD4+ lymphocytes. CD8 cytotoxicity produces an acutization of a smoldering infection and/or an immunopathological reaction similar to ADEM.

About 90 % of meningiomas are benign (WHO grade I), atypical and anaplastic variants exist (WHO grade II/III, 10 %). Tumour grade has important implications for management. Non-invasive diagnosis of tumour grade is still not feasible. The purpose of this survey was to analyse epidemiological risk factors such as sex, age and location for a higher grade (WHO grade II/III) meningioma in a large surgical series. A retrospective study comprising 1,663 patients operated on for an intracranial meningioma in a single tertiary-care centre. The population was analysed for correlations including WHO grade, histological subtype, tumour localisation, patient age and gender. Additionally correlations between Ki67 index/WHO grade and localisation were analysed. A binary logistic regression analysis revealed non-skull base localisation (OR 1.779 [CI 1.069–2.960, p = 0.0027]) and age ≥65 years (OR 1.549 [CI 1.214–2.624, p = 0.012]) as significant risk factors for a higher WHO grade. Male gender showed a trend for a higher risk in χ2 analysis. An analysis of the Ki67 index revealed an increased index for non-skull base localisation compared with skull base (p

Background. The 1p19q non-codeleted gliomas with IDH mutation, defined as “molecular astrocytomas,” display frequent TP53 mutations and have an intermediate prognosis. We investigated the prognostic impact of copy number-neutral loss of heterozygosity (CNLOH) in 17p in this population. Methods. We analyzed 793 gliomas (206 grade II, 377 grade III, and 210 grade IV) by single nucleotide polymorphism array and for TP53 mutations. Results. Homodisomy revealed by CNLOH was observed in 156 cases (19.7%). It was more frequent in astrocytomas and oligoastrocytomas (98/256, 38%) than oligodendrogliomas (28/327, 8.6%; p < .0001) or glioblastoma multiforme (30/210, 14.3%; p < .0001), tightly associated with TP53 mutation (69/71 vs. 20/79; p = 2 × 10−16), and mutually exclusive with 1p19q codeletion (1/156 vs. 249/556; p < .0001). In the group of IDH-mutated 1p19q non-codeleted gliomas, CNLOH 17p was associated with longer survival (86.3 vs. 46.2 months; p = .004), particularly in grade III gliomas (overall survival >100 vs. 37.9 months; p = .007). These data were confirmed in an independent dataset from the Cancer Genome Atlas. Conclusion. CNLOH 17p is a prognostic marker and further refines the molecular classification of gliomas.

The presence of cysts is a rare occurrence for intracranial meningiomas in adults. We report our experience in a large consecutive series of cystic meningiomas. We prospectively collected data for a dedicated database of cystic meningioma cases between January 2004 and December 2011 in two tertiary neurosurgical centers. Studied data included preoperative imaging, surgical records, and pathology reports. Among 1214 surgeries for intracranial meningioma, we identified 43 cases of cystic meningioma, corresponding to an incidence of 3.5 %. The most common localization was the hemispheric convexity (17/43 cases). Twenty-eight patients had intratumoral cysts, nine peritumoral, and five mixed intra and extratumoral. In 29 patients with available diffusion imaging, ADC coefficients were significantly lower in grade II-III tumors compared to grade I (p = 0.01). Complete resection of the cystic components was possible in 27/43 patients (63 %); partial resection in 4/43 (9 %); in 6/43 (14 %) cyst resection was not possible but multiple biopsies were performed from the cystic walls; in another 6/43 (14 %) the cystic wall was not identified during surgery. Cells with neoplastic features were identified within the cyst walls at pathology in 26/43 cases (60 %). All patients were followed-up for 24 months; long-term follow-up was available only in 32 patients for an average period of 49 months (range, 36–96 months). No recurrence requiring surgery was observed. Cystic meningiomas are rare. Cells with neoplastic features are often identified within the cyst walls. Complete cyst resection is recommendable when considered technically feasible and safe.

Cerebellopontine angle medulloblastoma is a very uncommon presentation of medulloblastoma, especially in children. We report such a case in a 14-year-old boy. Clinical onset by acute hearing loss and MRI features were, furthermore, unusual findings. The tumour had an homogeneous signal on T1 and FLAIR sequences a high-signal intensity on diffusion-weighted images with slightly restricted ADC value (0.85 × 10³ mm²/s) and enhanced slightly and homogeneously after contrast. A subtotal removal of the tumour, followed by entire neuroaxis irradiation and chemotherapy were achieved. MRI data of the literature reported cases were reviewed. Features on conventional MRI sequences do not allow differentiating CPA medulloblastoma from other rare tumour of this location. We point out that ADC value and Spectroscopy might be useful differentiating CPA tumours, especially from ependymoma in children.

International audience; no abstract

International audience; Chordomas are slow-growing malignant neoplasms. Determination of histopathologic prognostic factors using a large cohort study has been limited by their low incidence. In this retrospective study, we investigated the clinical, histopathologic, and immunohistochemical prognostic factors in 287 chordomas from 111 patients assessed by central pathologic review. Expression patterns of a variety of markers, including vascular endothelial growth factor (VEGF), mTOR pathway, c-kit, HER2, epidermal growth factor receptor (EGFR) and STAT3, and KRAS, BRAF, EGFR, and PIK3CA mutations were analyzed. On univariate analysis, the results confirm surgery as the best treatment, as judged by patient progression-free survival (PFS) and overall survival (OS). Proton therapy, the presence of a dedifferentiated component, mitotic figures, and Ki67 and p53 labeling indices correlated with PFS . Necrosis and apoptosis correlated with OS. Based on these findings, we propose a histopathologic grading system that correlates with PFS and OS. On multivariate analysis, extent of resection, tumor grade, and proton therapy were independent prognostic factors of PFS; extent of resection, tumor location, and grade were independent prognostic factors of OS. Based on the expression of EGFR, pSTAT3, VEGF, and mTOR pathway proteins, (in 85.9%, 79.1%, 85.7%, and 46% of chordomas, respectively), and 2 new mutations in the PIK3CA gene, we also provide evidence for potential therapeutic targets.

The new WHO classification of diffuse gliomas has been refined and now includes the 1p/19q codeletion, IDH1/2 mutation, and histone H3-K27M mutation. Our objective was to assess the prognostic value of the updated 2016 WHO classification in the French POLA cohort. All cases of high-grade oligodendroglial tumors sent for central pathological review and included into the French nationwide POLA cohort were reclassified according to the updated 4th WHO classification. In total, 1041 patients were included, with a median age at diagnosis of 50.4 years (range 17.1–84.4). Based on the new histomolecular classification, diagnoses included anaplastic oligodendroglioma IDH mutant and 1p/19q-codeleted (32.5 %), anaplastic astrocytoma IDH mutant (IDH mut) (11.0 %), anaplastic astrocytoma IDH wild type (IDH wt) (5.3 %), glioblastoma IDH mut (17.1 %), and glioblastoma IDH wt (33.2 %). Ten patients presented with a diffuse midline tumor, H3 K27M mutant. The new WHO classification was prognostic for progression-free survival (PFS) and overall survival (OS) (p

Purpose: Our objective was to identify the genetic changes involved in primary central nervous system lymphoma (PCNSL) oncogenesis and evaluate their clinical relevance. Experimental Design: We investigated a series of 29 newly diagnosed, HIV-negative, PCNSL patients using high-resolution single-nucleotide polymorphism (SNP) arrays (n = 29) and whole-exome sequencing (n = 4) approaches. Recurrent homozygous deletions and somatic gene mutations found were validated by quantitative real-time PCR and Sanger sequencing, respectively. Molecular results were correlated with prognosis. Results: All PCNSLs were diffuse large B-cell lymphomas, and the patients received chemotherapy without radiotherapy as initial treatment. The SNP analysis revealed recurrent large and focal chromosome imbalances that target candidate genes in PCNSL oncogenesis. The most frequent genomic abnormalities were (i) 6p21.32 loss (HLA locus), (ii) 6q loss, (iii) CDKN2A homozygous deletions, (iv) 12q12-q22, and (v) chromosome 7q21 and 7q31 gains. Homozygous deletions of PRMD1, TOX, and DOCK5 and the amplification of HDAC9 were also detected. Sequencing of matched tumor and blood DNA samples identified novel somatic mutations in MYD88 and TBL1XR1 in 38% and 14% of the cases, respectively. The correlation of genetic abnormalities with clinical outcomes using multivariate analysis showed that 6q22 loss (P = 0.006 and P = 0.01) and CDKN2A homozygous deletion (P = 0.02 and P = 0.01) were significantly associated with shorter progression-free survival and overall survival. Conclusions: Our study provides new insights into the molecular tumorigenesis of PCNSL and identifies novel genetic alterations in this disease, especially MYD88 and TBL1XR1 mutations activating the NF-κB signaling pathway, which may be promising targets for future therapeutic strategies. Clin Cancer Res; 18(19); 5203–11. ©2012 AACR.

Summary Purpose: An International League Against Epilepsy (ILAE) consensus classification system for focal cortical dysplasias (FCDs) has been published in 2011 specifying clinicopathologic FCD variants. The aim of the present work was to microscopically assess interobserver agreement and intraobserver reproducibility for FCD categories among an international group of neuropathologists with different levels of experience and access to epilepsy surgery tissue. Methods: Surgical FCD specimens covering a broad histopathology spectrum were retrieved from 22 patients with epilepsy. Three surgical nonepilepsy specimens served as controls. A total of 188 slides with routine or immunohistochemical stainings were digitalized with a slide scanner to allow Internet-based microscopy review. Nine experienced neuropathologists were invited to review these cases twice at a time gap of 3 months and different orders of case presentation. The 2011 ILAE FCD consensus classification served as instruction. Kappa analysis was calculated to estimate interobserver and intraobserver agreement levels. In a third evaluation round, 21 additional neuropathologists with different experience and access to epilepsy surgery reviewed the same case series. Key Findings: Interobserver agreement was good (I° = 0.6360), with 84% consensus of diagnoses during the first evaluation (21 of 25 cases). Kappa values increased to 0.6532 after reevaluation, and consensus was obtained in 24 (96%) of 25 cases. Overall intraobserver reproducibility was also good (I° = 0.7824, ranging from 0.4991 to 1.000). Fewest changes in the classification were made in the FCD type II group (2.2% of 225 original diagnoses), whereas the majority of changes occurred in FCD type III (13.7% of 225 original diagnoses). In the third evaluation round, interobserver agreement was reflected by the level of experience of each neuropathologist, with I° values ranging from moderate (0.5056; high level of experience >40 cases/year) to low (0.3265; low level of experience

M. Fevre-Montange, A. Vasiljevic, D. Frappaz, J. Champier, A. Szathmari, M.-H. Aubriot Lorton, F. Chapon, A. Coulon, I. Quintin Roue, M.-B. Delisle, D. Figarella-Branger, A. Laquerriere, C. Miquel, J.-F. Michiels, M. Peoch, M. Polivka, F. Fauchon and A. Jouvet (2012) Neuropathology and Applied Neurobiology38, 87–94 Utility of Ki67 immunostaining in the grading of pineal parenchymal tumours: a multicentre study Aims: Pineal parenchymal tumours (PPTs) are rare neoplasms that are divided into pineocytoma (PC), pineoblastoma (PB) and PPT of intermediate differentiation (PPTID). Factors affecting the survival of patients with PPTs are morphological subtype and histological grading according to mitotic index and neurofilament immunostaining. Grading criteria to distinguish PPTIDs are difficult to define, particularly when using small specimens. The Ki67 labelling index (LI) might be helpful in distinguishing between grade II and III PPTIDs. Our study was performed to assess the predictive value of the Ki67 LI in a large cooperative series of PPTs and to evaluate whether inclusion of this data would improve and refine the World Health Organization classification. Methods: A retrospective analysis of 33 PPTs was performed. The histological features of the tumours were reviewed and Ki67 LI scoring was evaluated by immunohistochemistry. Data were correlated with the patients' survival. Results: The mean Ki67 LI was significantly different for tumour grades (0 in PC, 5.2 ± 0.4 in PPTID grade II, 11.2 ± 2.0 in PPTID grade III, 36.4 ± 6.2 in PB; P

International audience; INTRODUCTION:Papillary Glioneuronal Tumor (PGNT) is a grade I tumor which was classified as a separate entity in the World Health Organization Classification of the Central Nervous System 2007 in the group of mixed glioneuronal tumors. This tumor is rare and subclassifying PGNT represents a challenge. Recently, a fusion between SLC44A1 and PRKCA which encodes a protein kinase C involved in MAPK signaling pathway has been described in two studies (five cases). The current study aimed at raising the cytogenetic, histological and molecular profiles of PGNT and to determine if SLC44A1-PRKCA fusion represented a specific diagnostic marker to distinguish it from other glioneuronal tumors.RESULTS:We report on four pediatric cases of PGNT, along with clinico-radiologic and immunohistological features for which SLC44A1-PRKCA fusion assessment by fluorescence in situ hybridization, BRAF V600E and FGFR1 mutation by immunohistochemistry and direct DNA sequencing and KIAA1549-BRAF fusion by RT-PCR were performed. MAPK signaling pathway activation was investigated using phospho-ERK immunohistochemistry and western blot. We analyzed fifteen cases of tumors with challenging histological or clinical differential diagnoses showing respectively a papillary architecture or periventricular location (PGNT mimics). fluorescence in situ hybridization analysis revealed a constant SLC44A1-PRKCA fusion signal in all PGNTs. None of PGNT mimics showed the SLC44A1-PRKCA fusion signal pattern. All PGNTs were negative for BRAF V600E and FGFR1 mutation, and KIAA1549-BRAF fusion. Phospho-ERK analysis provides arguments for the activation of the MAPK signaling pathway in these tumors.CONCLUSIONS:Here we confirmed and extended the molecular data on PGNT. These results suggest that PGNT belong to low grade glioma with MAPK signaling pathway deregulation. SLC44A1-PRKCA fusion seems to be a specific characteristic of PGNT with a high diagnostic value and detectable by FISH.

Objectives Infectious myositis can be a life-threatening condition. We describe the clinical presentation, diagnosis, treatment, and outcome of a patient with Aspergillus -related myositis and review the relevant literature on Aspergillus -related myositis. Methods We report on a patient with acquired immunodeficiency syndrome who presented with Aspergillus myo-fasciitis, which was unusual because of its relapsing–remitting course and favorable outcome. We analyze the clinical features, diagnosis, and treatment of 9 additional patients identified through a PubMed literature review between 1964 and early 2010. Results A 64-year-old human immunodeficiency virus positive African woman was hospitalized for a relapsing-remitting history of bilateral myo-fasciitis for more than 15 years. She had already undergone 3 previous muscle biopsies without definite diagnosis. A computed tomographic scan-guided biopsy revealed numerous septae hyphae with focal necrosis. Cultures yielded Aspergillus flavus as the underlying pathogen and the diagnosis of Aspergillus -related myo-fasciitis was finally made. On reviewing the literature, only 9 other cases have been described. However, no similar case with such a chronic and favorable course was reported. Conclusions As compared with the reported cases in the literature, our case is unusual because of its relapsing–remitting course for more than 15 years and favorable outcome. Our case emphasizes the difficulty of the diagnosis, and the importance of early and appropriate management of this rare myositis, which should be systematically evoked in patients with immune deficiency.

Gliomatosis cerebri is a rare glial neoplasm, characterized by diffuse brain infiltration with relative preservation of the underlying cytoarchitecture. Its clinical and radiologic features are not specific and its antemortem diagnosis is difficult. We report a case of gliomatosis cerebri in a 68-year-old woman presenting with gait disturbances and episodic seizures. MRI showed bilateral white matter hypersignal intensities on Flair sequences and brain biopsy revealed a poorly cellular proliferation of neoplasic glial cells strongly expressing OLIG-2, Ki-67 and occasionally GFAP, without alpha-internexin expression. The patient status worsened rapidly and she died 2 months after the initial symptoms. Postmortem brain examination confirmed gliomatosis cerebri and revealed a focal glioblastoma in the frontal cortex, with nuclear p53 expression in the highest malignant areas. Gliomatosis cerebri should be included in the differential diagnostic of diffuse brain lesions. Antemortem diagnosis, although difficult, can be assessed by IRM and careful biopsy examination. Progression to glioblastoma has been seldom reported, enhancing the controversy about the etiopathogenesis of this rare tumour.