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Medulloblastoma (MB) comprises a group of heterogeneous paediatric embryonal neoplasms of the hindbrain with strong links to early development of the hindbrain1–4. Mutations that activate Sonic hedgehog signalling lead to Sonic hedgehog MB in the upper rhombic lip (RL) granule cell lineage5–8. By contrast, mutations that activate WNT signalling lead to WNT MB in the lower RL9,10. However, little is known about the more commonly occurring group 4 (G4) MB, which is thought to arise in the unipolar brush cell lineage3,4. Here we demonstrate that somatic mutations that cause G4 MB converge on the core binding factor alpha (CBFA) complex and mutually exclusive alterations that affect CBFA2T2, CBFA2T3, PRDM6, UTXand OTX2. CBFA2T2is expressed early in the progenitor cells of the cerebellar RL subventricular zone in Homo sapiens, and G4 MB transcriptionally resembles these progenitors but are stalled in developmental time. Knockdown of OTX2in model systems relieves this differentiation blockade, which allows MB cells to spontaneously proceed along normal developmental differentiation trajectories. The specific nature of the split human RL, which is destined to generate most of the neurons in the human brain, and its high level of susceptible EOMES+KI67+unipolar brush cell progenitor cells probably predisposes our species to the development of G4 MB.

In cancer, recurrent somatic single-nucleotide variants—which are rare in most paediatric cancers—are confined largely to protein-coding genes1–3. Here we report highly recurrent hotspot mutations (r.3A>G) of U1 spliceosomal small nuclear RNAs (snRNAs) in about 50% of Sonic hedgehog (SHH) medulloblastomas. These mutations were not present across other subgroups of medulloblastoma, and we identified these hotspot mutations in U1 snRNA in only <0.1% of 2,442 cancers, across 36 other tumour types. The mutations occur in 97% of adults (subtype SHHδ) and 25% of adolescents (subtype SHHα) with SHH medulloblastoma, but are largely absent from SHH medulloblastoma in infants. The U1 snRNA mutations occur in the 5′ splice-site binding region, and snRNA-mutant tumours have significantly disrupted RNA splicing and an excess of 5′ cryptic splicing events. Alternative splicing mediated by mutant U1 snRNA inactivates tumour-suppressor genes (PTCH1) and activates oncogenes (GLI2and CCND2), and represents a target for therapy. These U1 snRNA mutations provide an example of highly recurrent and tissue-specific mutations of a non-protein-coding gene in cancer.

Le syndrome de la mort inattendue du nourrisson (MIN) est défini selon la Haute Autorité de santé (HAS) comme « une mort survenant brutalement chez un nourrisson alors que rien, dans ses antécédents connus, ne pouvait le laisser prévoir ». Il s’agit d’un diagnostic d’exclusion. Il existe de grandes disparités interrégionales tant d’un point de vue épidémiologique que dans la prise en charge des MIN malgré les recommandations professionnelles établies par la HAS en février 2007. Pour l’examen de l’encéphale, les consignes de la HAS sont peu adaptées à la pratique courante et de recherche. Le rôle du pathologiste, comme tout intervenant dans le cadre des MIN, est d’éliminer un traumatisme en particulier en lien avec une maltraitance et de déterminer la cause du décès. Les lésions neuropathologiques majeures par définition n’existent pas. Les lésions d’hypoxie/ischémie sont les plus fréquentes et sont peu spécifiques. L’accessibilité de l’immunomarquage anti-APP a permis de souligner le rôle de l’anoxie dans l’apparition des lésions axonales diffuses. De nombreuses études recherchent un substratum neurologique de la MIN (neuropathologiques et/ou neurobiochimiques). Cet article a pour objectif de définir un protocole de prélèvement détaillé à partir de consensus étrangers et des données actuelles de la science afin d’aider les anatomopathologistes et de favoriser une banque de données homogènes en France.

Accurate pathological diagnosis is crucial for optimal management of patients with cancer. For the approximately 100 known tumour types of the central nervous system, standardization of the diagnostic process has been shown to be particularly challenging—with substantial inter-observer variability in the histopathological diagnosis of many tumour types. Here we present a comprehensive approach for the DNA methylation-based classification of central nervous system tumours across all entities and age groups, and demonstrate its application in a routine diagnostic setting. We show that the availability of this method may have a substantial impact on diagnostic precision compared to standard methods, resulting in a change of diagnosis in up to 12% of prospective cases. For broader accessibility, we have designed a free online classifier tool, the use of which does not require any additional onsite data processing. Our results provide a blueprint for the generation of machine-learning-based tumour classifiers across other cancer entities, with the potential to fundamentally transform tumour pathology.

Meningeal solitary fibrous tumors–hemangiopericytomas (SFT-HPC) and meningiomas can be difficult to distinguish on histologic examination. STAT6 immunohistochemistry (IHC) is a reliable diagnostic marker of SFT-HPCs. Recently, GRIA2 has also been reported to be a diagnostic marker of SFT-HPC, although no extensive data are available for meningeal SFT-HPCs yet. The aim of this study was to test their diagnostic performance in a large cohort of SFT-HPCs and meningiomas. IHC analyses for GRIA2 and STAT6 were performed on tissue microarrays containing 76 SFT-HPCs and 181 meningiomas. Results were compared with previous data with ALDH1 and CD34. Two different anti-STAT6 antibodies were tested: SC-20 polyclonal and YE361 monoclonal antibody. Ninety-six percent of meningeal SFT-HPCs but no meningioma displayed nuclear STAT6 positivity. With SC-20 antibody, concomitant cytoplasmic staining for STAT6 was observed in >50% of all cases, including meningiomas. However, using YE361 antibody, cytoplasmic staining was absent, and nuclear signal intensity was stronger leading to better interpretation of STAT6 IHC. GRIA2 was positive in 84% of SFT-HPCs and in 16% of meningiomas. STAT6 had excellent sensitivity (96%) and specificity (100%), ALDH1 and GRIA2 had same sensitivity (84%), but ALDH1 and CD34 had better specificity than GRIA2 (97% and 96% vs. 84%, respectively). For the differential diagnosis of SFT-HPCs versus meningiomas, the best diagnostic approach is to perform STAT6, followed by ALDH1 and CD34 in the case of uncommon STAT6-negative cases. Because of meningioma positivity, GRIA2 seems less useful in this indication.

Le gangliocytome du cervelet peut correspondre à la maladie de Lhermitte-Duclos, malformation hamartomateuse bénigne de l’adulte jeune, ou appartenir au groupe des gangliogliomes/gangliocytomes, tumeurs habituellement temporales de l’enfant qui se manifestent par des crises comitiales. Nous décrivons le cas d’un jeune garçon de 11ans ayant présenté un gangliocytome du cervelet découvert devant un tableau neurologique comportant des céphalées, une dyspraxie et des troubles de l’équilibre et de la marche. Le diagnostic a été porté sur le matériel chirurgical d’exérèse. La tumeur correspondait à une population de cellules ganglionnaires matures d’aspect dysplasique, accompagnée d’infiltrats inflammatoires lymphocytaires périvasculaires et sans contingent tumoral glial identifié. En immunohistochimie, les cellules ganglionnaires exprimaient les neurofilaments, la protéine MAP2, la synaptophysine, la chromogranine A et la protéine S100. La mutation V600E de BRAFn’a pas été détectée. Les caractéristiques cliniques, radiologiques, histopathologiques des deux principaux diagnostics sont discutées.

Inactivation of SMARCB1tumor-suppressor gene was originally described as highly specific for rhabdoid tumors (RTs). Nevertheless, recent reports have illustrated that SMARCB1alterations also characterize other tumors; in particular, some familial schwannomatosis and epithelioid malignant peripheral nerve sheath tumors, both from peripheral nervous system (PNS) origin, lack BAF47 expression. To document the putative role of SMARCB1in PNS, we reviewed PNS tumors referred to our institution for a molecular analysis of SMARCB1because of histologic features compatible with RT.

Neuroepithelial papillary tumor of the pineal region (PTPR) has been defined as a distinct entity that is increasingly being recognized, with 96 cases now reported. This tumor shares morphologic features with both ependymomas and choroid plexus tumors. PTPR is characterized by an epithelial-like growth pattern in which the vessels are covered by layers of tumor cells forming perivascular pseudorosettes. These tumors exhibit various combinations of papillary and solid architecture, making the differential diagnosis of PTPR difficult to establish. We report the detailed description of the histopathologic features of a large series of PTPRs from 20 different centers and distinguish 2 subgroups of tumors with either a striking papillary growth pattern or a papillary and solid growth pattern. We highlight the findings that PTPRs have unusual vessels with multiple lumina and frequently show detachment of the border of the tumoral cells from the vascular wall. The 2 PTPR subgroups present similar clinical characteristics and immunophenotypes. We confirmed and extended the results of previous ultrastructural studies on the presence of intercellular junctions at the apical part of tumoral cells. The expression of the tight junction proteins claudin-1, claudin-2, and claudin-3 was investigated by immunohistochemistry. Claudin-1 and claudin-3, but not claudin-2, were expressed in PTPRs and in the fetal subcommissural organ, potentially the origin of this tumor. In contrast, all 3 claudins were expressed in choroid plexus papillomas. Claudin expression may help in the diagnosis of PTPRs and can be used in combination with other markers, such as CK18, NCAM, E-cadherin, MAP-2, and Kir 7.1.

Central neurocytoma (CN) is a rare intraventricular tumor presenting a benign histologic appearance and favorable prognosis after surgery. In contrast, “atypical” CN is defined by a high MIB1 proliferation index andor histologic features of malignancy, which are associated with a poorer outcome. This variant of CN remains somewhat controversial. To better characterize CN and its “atypical” variant, a retrospective multicenter study was conducted on 71 patients presenting with CN. A statistical analysis of clinical, radiologic, and histologic data was conducted to validate prognostic factors. The immunohistochemical phenotype of CNs, analyzed by tissue microarrays, and the MIB1 index were evaluated for 45 cases. Tissue microarrays validated the expression of neuronal markers synaptophysin and NeuN, but not that of glial markers glial fibrillary acidic protein and oligodendrocyte transcription factor 2. In the univariate analysis, a tumor volume ≥30 cm3(P=0.025), incomplete surgery (P=0.033), and a mitotic count ≥3 per 10 high-power fields (P=0.009) were predictors of a higher risk of recurrence, unlike the other usual histologic features of malignancy and the high MIB1 index. Partial surgery was the only criterion associated with a poorer outcome in the multivariate model. Our results, based on a large multicenter series, show the striking homogeneity of CNs and do not support the use of histologic criteria as reliable markers to define an “atypical” group of CNs. Our study suggests that the extent of surgery is the main factor to be considered in the prognostic assessment of patients with CN.

Several types of glioneuronal tumors are known to induce intractable partial seizures in children and adults. The most frequent are dysembryoplastic neuroepithelial tumors (DNETs) and gangliogliomas. We report here a new clinicopathological entity within the spectrum of glioneuronal tumors observed in 10 children who underwent surgery for refractory epilepsy. These tumors demonstrate a unique, pathognomonic histological pattern and a specific appearance at magnetic resonance imaging (MRI). The most striking neuropathological feature is an angiocentric polarity of the tumor with gliofibrillary acidic protein (GFAP) positive fusiform and bipolar astrocytic cells arranged around blood vessels (perivascular cuffing with tumoral astrocytes). Characteristic MRI findings include involvement of cortical gray and white matter, intrinsically high signal on T1‐weighted images, as well as a stalk like extension to the ventricle. Immunohistochemical neuronal markers (neurofilament protein, synaptophysin and chromogranin) confirm the presence of a neuronal cell component. Therefore, the term angiocentric neuroepithelial tumor (ANET) is proposed.

1. Tryptophan hydroxylase (TPOH) is the first enzyme in the melatonin synthesis pathway and the rate-limiting enzyme in serotonin synthesis. We established in this study an in vitro model of ovine pinealocytes to investigate the role of TPOH in melatonin production. 2. We demonstrated that TPOH is highly expressed both in vivo and in vitro at the protein and mRNA levels. In vitro pinealocytes show ultrastructural features similar to those previously described in vivo. 3. Moreover, our in vitro model allowed us to study the regulation mechanisms for melatonin synthesis in sheep pinealocytes and to demonstrate that both transcriptional and posttranscriptional mechanisms are involved. 4.In particular, our results suggest that TPOH plays an essential role in the regulation of melatonin synthesis.

Somatostatin receptors (SSts) have been found in a variety of brain tumors, e.g., meningiomas, medulloblastomas and astrocytomas. Our aim was to investigate their expression in ependymomas. Using RT-PCR, expression of mRNA for the different SSt subtypes was analyzed and quantified in 28 ependymomas and correlated with different variables (age, tumor location, histological grade, recurrence and survival). In addition, in 8 cases, protein expression was studied in vitro, using immunohistochemistry, and in vivo, by somatostatin scintigraphy. mRNAs for all 5 subtypes were variably expressed in each ependymoma. The Southern blotting signal obtained after SSt1 and SSt2 amplification was higher than that for the other receptor subtypes. No significant correlation was seen between the level of SSt1 and SSt2 mRNA expression and age, location, histological grading, recurrence or survival. In the 8 cases, SSt1 staining was negative in 3 and low in 5. Staining for SSt2A was positive but low in every specimen analyzed. SSt1 and SSt2 immunoreactivity was seen only in the cytoplasm of tumoral cells. Somatostatin scintigraphy showed clear uptake, which agreed with MRI data in the majority of cases. However, no correlation was seen between tracer uptake intensity and histological grade, SSt1 and SSt2 mRNA expression or immunostaining intensity. This evidence for the expression of SSt2 receptors in ependymomas opens interesting prospects for their follow-up. © 2001 Wiley-Liss, Inc.

Purpose.Classical and new therapies in anaplastic astrocytomas and glioblastomas do not yield sufficient results. Agents able to redifferentiate neoplastic cells in vitroare known. We proposed alfacalcidol, a vitamin D analog able to bind to nuclear receptors regulating mitotic activity, in the treatment of malignant gliomas. Patients and methods.Patients with glioblastomas and anaplastic astrocytomas were enrolled in a phase II trial involving surgery or biopsy, radiotherapy (64 Gy), chemotherapy with VM26-CCNU or fotemustine, and alfacalcidol at the daily dose of 0.04 μg/kg. MRI took place every 6 months. ResultsEleven patients were included and completed the study. The series involved 10 glioblastomas and 1 anaplastic astrocytoma. Three patients out of 11 patients (27%), 2 glioblastomas and 1 astrocytoma grade III, exhibited a particular response, consisting in the progressive regression of the radiological lesion, with a decrease of the gadolinium-enhanced area. Simultaneously, the patients showed a complete clinical remission, observed respectively for 7, 5 and 4 years. In the series of 10 patients with glioblastomas, 2 cases showed this response; after 4 years, 2 of 10 patients with glioblastomas (20%) were alive; the median survival time is 21 months. Normal or subnormal calcemia was observed, at the dose proposed, so that no interruption of the drug was necessary. ConclusionsAlfacalcidol, an in vitroagent of redifferentiation, is safe and seems able to induce in some patients, in synergy with classical surgery–radiotherapy–chemotherapy treatments, a particular progressive and durable regression of the tumor. The responders might represent about 20% of malignant gliomas.

Object.Somatostatin receptors have been found on a variety of tumours like neuroendocrine breast or brain tumours. Their detection opens new diagnostic and therapeutic paths. The aim of this work was to investigate their expression in medulloblastomas. Methods.Using both techniques, reverse transcriptase-polymerase chain reaction and immunohistochemistry, we analysed mRNA of different subtypes of somatostatin receptors in 15 medulloblastomas and the localisation of the subtype SSTR2 receptor at the cellular level in 13 medulloblastomas. All five subtypes mRNA were variably expressed in each medulloblastoma. The signal obtained after Southern blotting for SSTR2 receptor amplification was the highest as compared to the signal obtained for the other receptor subtypes. Immunostaining for SSTR2A receptor was present in every tumour specimen and was specifically located to the cellular membrane of neoplastic cells. No staining was identified at the level of peritumoral veins. Conclusion.The evidence of predominant expression of SSTR2 receptors in medulloblastomas opens interesting prospects for their diagnosis and therapy.

The WHO classification of CNS tumors divides pineal parenchymal tumors (PPT) into pineocytoma (PC), pineoblastoma (PB) and mixed pineocytomapineoblastoma or PPT with intermediate differentiation. The reported incidence of mixed/intermediate PPT varies and this may reflect the difficulty in classifying tumors of this type. In an attempt to overcome the problem of the classification of PPT with intermediate differentiation, we describe the relationship between histological features and patient survival in a large cooperative series of 66 PPT from 12 neurosurgical centres. All tumors were studied with both light microscopy and immunohistochemically using antibodies against glial markers or neural/neuroendocrine markers. Our series included 11 PC, 39 mixed/intermediate PPT and 16 PB. A number of mitoses greater than 6 and the presence of necrosis were associated with a poorer outcome, while positive immunostaining for neurofilaments was associated with a better survival. We propose a new prognostic grading of 4 grades, grade I for PC, grade II for PPT with fewer than 6 mitoses and positive immunolabelling for neurofilaments, grade III for PPT with either 6 or more than 6 mitoses or fewer than 6 mitoses but without immunostaining for neurofilaments and grade IV for PB.

Xeroderma pigmentosum (XP) is a rare hereditary disease characterized by a very high frequency of skin tumours due to a defect in the nucleotide-excision-repair process. Some of these patients have also been reported to develop internal tumours with higher frequency than the normal population. Reported here are the clinical features and molecular analysis of an XP patient who developed multiple skin cancers as well as a thalamic glioma. Complementation analysis with recombinant retrovirus, cloning efficiency and unscheduled DNA synthesis after UV-C indicate that the patient belongs to the C group. Characterization of the p53 mutations in the 2 tumours of the patient leads to speculation on the aetiological agents involved in tumour initiation. The skin tumour is clearly induced by the presence of unrepaired UVB-induced DNA damage on the non-transcribed strand of the p53 gene, while the glioma may be induced by unrepaired DNA lesions produced by free radicals. Int. J. Cancer 81:345–350, 1999. © 1999 Wiley-Liss, Inc.

Brain metastases are uncommon among children with solid tumors. However, improvements in survival have increased the period of time during which children are at risk for developing these metastases. The authors reviewed brain metastases in children with solid tumors treated at the Centre Léon Bérard during the 9 years between 1987 and 1995. Among 486 patients with solid tumors, 162 eventually developed distant metastases in their disease process, including 12 brain metastases detected by imaging. The tumor type, clinical setting, imaging characteristics, treatment modalities, and outcome were assessed for each patient. The most common tumors causing brain metastases were Ewing's sarcoma (in three patients), neuroblastoma (in three patients), and osteogenic sarcoma (in three patients). At the time of initial diagnosis, 9 of the 12 patients had metastatic disease. All but one patient initially received intensive multiagent chemotherapy, including high dose chemotherapy with bone marrow rescue in six patients. The median time from initial diagnosis to the detection of brain metastases was 15 months. These metastases were clinically detectable in 10 patients and subclinical in 2 patients. Brain metastases were present at the time of first relapse in five patients. In two patients, the brain was the only site of relapse. All other patients had extensive systemic disease. Seven patients had multiple brain metastases. Two children underwent surgical resection of solitary metastases, and eight were irradiated. One child achieved complete remission following chemotherapy and irradiation. All other children died, mostly of their systemic disease, within a median period of 3 months. The introduction of effective systemic chemotherapy has changed the patterns of brain metastases in children. The increasing incidence of these metastases in patients with sarcoma and neuroblastoma suggests that the brain is a pharmacologically protected site in patients initially diagnosed with metastatic disease. Cancer 1997; 79:403-10. © 1997 American Cancer Society.

In the human striatum, we immunohistochemically demonstrated many neurons that were immunoreactive for aromatic l-amino acid decarboxylase (AADC; the second step dopamine-synthesizing enzyme) but not for tyrosine hydroxylase (TH; the first step dopamine-synthesizing enzyme). The number of AADC-positive neurons was especially large in the ventral striatum including the nucleus accumbens. The significance of AADC-positive neurons are discussed in relation to the acting sites of l-dopa and antipsychotic drugs.

Factors that could optimize the management of pediatric spinal cord astrocytoma remain unclear and controversial. To determine the factors that influence the prognosis of pediatric patients with spinal cord astrocytomas, a series of 73 consecutive patients at 13 French treatment centers with histologically proven spinal cord astrocytomas was retrospectively reviewed. Hospital records, operative records, and results of radiologic investigations were available in all cases. Follow-up was achieved in 94% of cases. Seventy percent of the patients had low grade (1 or 2) tumors. Total or subtotal surgical resection was achieved in 43%. Thirty-six patients were irradiated following surgery. Fifty-one patients were alive at a median follow-up of 54 months. Twenty-three patients relapsed. Univariate analysis showed that good outcome was correlated with male gender, age younger than 7 years, duration of presenting symptoms longer than 2 months, the presence of spinal deformities, and low grade histology, whereas sensory loss was associated with decreased survival. Multivariate analysis using the Cox proportional hazards model confirmed that histology (relative risk [RR] = 7.69) and the interval between first symptoms and diagnosis (RR = 4.93) were significant independent prognostic factors. The extent of surgery or radiotherapy had no clear influence on survival. This review sheds light on the prognoses of pediatric patients with spinal cord astrocytomas and may help to determine therapeutic strategies based on patients' clinical, radiologic, and pathologic features. Cancer 1998;83:2391-2399. © 1998 American Cancer Society.

Papillary tumor of the pineal region (PTPR) is a recently described tumor entity thought to arise from the specialized ependyma of the subcommissural organ. Whereas histologic features of PTPR are well defined, data on the prognostic value of PTPR remain scarce. We therefore investigated clinicopathologic features, including data on progression-free survival and overall survival, in a retrospective series of 31 PTPR. The age of the 14 males and 17 females ranged from 5 to 66 years (median age, 29 years). Histologically, all tumors were characterized by an epithelial-like growth pattern in which the vessels were covered by layers of columnar or cuboidal tumor cells forming perivascular pseudorosettes. Most of the tumor cells showed strong expression of neuron-specific enolase, cytokeratins (particularly CK18), S-100 protein, and vimentin. Most PTPRs examined also expressed microtubule-associated protein-2. Expression of synaptophysin, epithelial membrane antigen, transthyretin, neural cell adhesion molecule, and nestin was encountered in some tumors. Gross total resection could be achieved in 21 of 31 cases; 15 patients received radiotherapy on resection of the primary tumor. Nevertheless, the majority of patients experienced recurrences; 5-year estimates for overall survival and progression-free survival were 73% and 27%, respectively. To conclude, the clinical course of PTPR is characterized by frequent local recurrence, and the value of radiotherapy on disease progression will need to be investigated in future prospective trials.

Several types of tumors are known to originate from the pineal region, among them pineal parenchymal tumors (PPTs) and papillary tumors of the pineal region (PTPRs), probably derived from the subcommissural organ. As a result of their rarity, their histologic diagnosis remains difficult. To identify molecular markers, using CodeLink oligonucleotide arrays, gene expression was studied in 3 PPTs (2 pineocytomas and one pineoblastoma), 2 PTPRs, and one chordoid glioma, another rare tumor of the third ventricle. Because PTPR and chordoid glioma may present ependymal differentiation, gene expression was also analyzed in 4 ependymomas. The gene patterns of the 3 PPTs fell in the same cluster. The pineocytomas showed high expression of TPH, HIOMT, and genes related to phototransduction in the retina (OPN4, RGS16, and CRB3), whereas the pineoblastoma showed high expression of UBEC2, SOX4, TERT, TEP1, PRAME, CD24, POU4F2, and HOXD13. Using reverse transcriptase-polymerase chain reaction on 13 PPTs, we demonstrated that PRAME, CD24, POU4F2, and HOXD13 might be candidates for grading PPT with intermediate differentiation. PTPRs, classified with chordoid glioma and separately from ependymomas, showed high expression of SPEDF, KRT18, and genes encoding proteins reported to be expressed in the subcommissural organ, namely ZFH4, RFX3, TTR, and CGRP. Our results highlight the usefulness of gene expression profiling for classify tumors of the pineal region and identify genes with potential use as diagnostic markers.