Meningeal SWI/SNF related, matrix-associated, actin-dependent regulator of chromatin, subfamily B member 1 (SMARCB1)-deficient tumours: an emerging group of meningeal tumours.

AIMS: Bi-allelic inactivation of SWI/SNF related, matrix-associated, actin-dependent regulator of chromatin, subfamily B member 1 (SMARCB1; also known as INI1) and loss of immunohistochemical expression of SMARCB1 define the group of SMARCB1-deficient tumours. Initially highlighted in malignant rhabdoid tumours, this inactivation has subsequently been observed in several intra and extracranial tumours. To date, primary meningeal SMARCB1-deficient tumours have not been described. We report two cases of meningeal SMARCB1-deficient tumours occurring in adults. METHODS: We performed immunohistochemical analyses, comparative genomic hybridization, fluorescence in situ hybridization and targeted next-generation sequencing. RESULTS: The first meningeal tumour was a solitary mass, composed of rhabdoid, adenoid, chordoid and sarcomatoid areas. The second case presented as multiple, bilateral, supra and infratentorial nodules, was composed of fusiform and ovoid cells embedded in a myxoid stroma. Tumour cells were positive for epithelial membrane antigen (EMA), vimentin and CD34 and negative for SMARCB1 and meningothelial, melanocytic, muscular, glial markers. In the first case, one allele of SMARCB1 was completely deleted, whereas in the second case, loss of expression of SMARCB1 was observed as a consequence of a homozygous deletion of SMARCB1. CONCLUSIONS: The phenotype and genotype of these two cases did not fit diagnostically with entities already known to be SMARCB1-deficient tumours. As both tumours shared common features, they are regarded as belonging to an emerging group of primary meningeal SMARCB1-deficient tumours, not described to date. To facilitate the identification and characterization of these tumours, we recommend SMARCB1 immunohistochemistry for primary meningeal tumours which are difficult to classify, especially if immunopositive for EMA and CD34.

Tectal plate tumours. Our experience with a paediatric surgical series.

INTRODUCTION: Exophytic tectal plate tumours are a particular kind of brain stem tumour that can be treated with microsurgical resection. This paper reports our surgical experience with a paediatric series stressing and underlines the fact that this surgery can be possible because the rate of surgical mortality is low in experienced hands with acceptable morbidity. MATERIAL AND METHODS: From 1997 to 2010, 27 patients were treated for exophytic tectal plate tumours. The clinical symptomatology was characterized by an intracranial hypertensive syndrome in 77% of cases, visual disorders in 36% of cases and a Parinaud's syndrome in 12% of cases. All patients were studied using a pre-operative cranio-spinal MRI with and without gadolinium. Hydrocephalus was present in 20 cases treated with a VP shunt in 6 cases and an ETV in the other cases. The surgical removal was total in 60% of cases, partial in 28% of cases and only a large biopsy in 12% of cases. From an histological point of view benign gliomas were diagnosed in 84% of cases and in 16% of cases were classified as WHO grade II and III. Eight patients needed complementary treatment, four with chemotherapy and four with chemotherapy associated to radiotherapy. As a surgical complication two patients had hydrocephalus, one patient had a sub-dural acute haematoma, two patients had an infectious complication requiring surgical treatment and antibiotic therapy, and 5 patients a mechanical shunt dysfunction. No post-surgical mortality was observed. RESULTS: The most recent results after a median survival of 4.3 years show that 22 patients are still alive while 5 patients died of a progressive disease. Twenty patients in school age continue to follow a normal school programme but 10 patients need assistance. CONCLUSION: Exophytic tectal plate tumours can be treated based on a microsurgical approach in paediatric patients. In experienced hands surgery can be performed with an acceptable morbidity and with zero percent mortality. In our experience, the sub-occipital transtentorial approach permits a wide view of the region and safe surgical removal.

Papillary tumor of the pineal region: Histopathological characterization and review of the literature.

BACKGROUND AND PURPOSE: The papillary tumor of the pineal region (PTPR) was described as a distinct new entity for the first time in 2003 by our team and has been included in the last 2007 WHO classification of tumors of the Central Nervous System. We describe the histopathological characterization of PTPR and present a review of the literature. METHODS: The description of the histological and immunological features of PTPR is based on the 2007 WHO classification. RESULTS: PTPR affects both children and adults, and mostly young adults in the third decade. PTPR is a neuroepithelial tumor occurring in the vicinity of the pineal gland, and characterized by its papillary architecture. The papillae are lined by multi-layered cuboidal to columnar epithelioid tumoral cells arranged in perivascular pseudorosettes. Immunohistochemistry shows strong reactivity for cytokeratins, particularly for cytokeratin 18. On electron microscopy, PTPR reveals ultrastructural features indicative of ependymal differentiation, including abundant microvilli at the apical cell pole. The differential diagnosis includes a variety of other papillary tumors, most notably papillary ependymoma, choroid plexus papilloma, papillary meningioma, and metastatic papillary carcinoma in adults. On the basis of ultrastructural and immunohistochemical features, it has been suggested that a PTPR arises from specialized cytokeratin-positive and nestin-positive ependymal cells that are derived from the subcommissural organ. Although the precise histological grading criteria of PTPR remain to be defined, its biological behavior may correspond to WHO grade II or III.

Histopathology of pineal germ cell tumors.

Germ cell tumors (GCTs) classically occur in gonads. However, they are the most frequent neoplasms in the pineal region. The pineal location of GCTs may be caused by the neoplastic transformation of a primordial germ cell that has mismigrated. The World Health Organization (WHO) recognizes 5 histological types of intracranial GCTs: germinoma and non-germinomatous tumors including embryonal carcinoma, yolk sac tumor, choriocarcinoma and mature or immature teratoma. Germinomas and teratomas are frequently encountered as pure tumors whereas the other types are mostly part of mixed GCTs. In this situation, the neuropathologist has to be able to identify each component of a GCT. When diagnosis is difficult, use of recent immunohistochemical markers such as OCT(octamer-binding transcription factor)3/4, Glypican 3, SALL(sal-like protein)4 may be required. OCT3/4 is helpful in the diagnosis of germinomas, Glypican 3 in the diagnosis of yolk sac tumors and SALL4 in the diagnosis of the germ cell nature of an intracranial tumor. When the germ cell nature of a pineal tumor is doubtful, the finding of an isochromosome 12p suggests the diagnosis of GCT. The final pathological report should always be confronted with the clinical data, especially the serum or cerebrospinal fluid levels of ß-human chorionic gonadotropin (HCG) and alpha-fetoprotein.

Anatomical, molecular and pathological consideration of the circumventricular organs.

BACKGROUND AND PURPOSE: Circumventricular organs (CVOs) are a diverse group of specialised structures characterized by peculiar vascular and position around the third and fourth ventricles of the brain. In humans, these organs are present during the fetal period and some become vestigial after birth. Some, such as the pineal gland (PG), subcommissural organ (SCO) and organum vasculosum of the lamina terminalis (OVLT), which are located around the third ventricle, might be the site of origin of periventricular tumours. In contrast to humans, CVOs are present in the adult rat and can be dissected by laser capture microdissection (LCM). METHODS: In this study, we used LCM and microarrays to analyse the transcriptomes of three CVOs, the SCO, the subfornical organ (SFO) and the PG and the third ventricle ependyma of the adult rat, in order to better characterise these organs at the molecular level. Furthermore, an immunohistochemical study of Claudin-3 (CLDN3), a membrane protein involved in forming cellular tight junctions, was performed at the level of the SCO. RESULTS: This study highlighted some potentially new or already described specific markers of these structures as Erbb2 and Col11a1 in ependyma, Epcam and CLDN3 in the SCO, Ren1 and Slc22a3 in the SFO and Tph, Anat and Asmt in the PG. Moreover, we found that CLDN3 expression was restricted to the apical pole of ependymocytes in the SCO.

Pineal parenchymal tumours and pineal cysts.

BACKGROUND AND PURPOSE: Pineal parenchymal tumours (PPTs) and pineal cysts represent one third of the pineal region lesions. PPTs are subdivided into pineocytoma (PC), pineoblastoma (PB) and PPT with intermediate differentiation (PPTID). We report morphological and immunochemical features which permit to grade these tumours. METHODS: The description of histopathological features and grading is based on a large cooperative series and on the WHO 2007 classification. RESULTS: PCs occur in adults between the third and the sixth decade of life. PBs typically occur in children. PPTIDs have a peak incidence in young adults between 20 and 40 years of age. There is no sex preference. PC is characterized by a uniform cell proliferation with large fibrillary pineocytomatous rosettes. PB is a high-density tumour composed of small blue cells with hyper-chromatic, round or carrot shaped nuclei. PPTIDs have lobulated or diffuse patterns. Grading is based on morphological features, count of mitoses and neurofilament protein (NFP) expression. PCs (grade I) have no mitosis and NFP is highly expressed in pineocytomatous rosettes. PBs (grade IV) are high mitotic tumours and present low or no expression of NFPs. PPTIDs are grade II when mitoses are fewer than 6 for 10 high-power fields and NFPs are expressed, and are grade III when mitoses are greater or equal to 6 or are fewer than 6 with NFPs lowly expressed. Pineal cysts may be differentiated from PPTs by the high expression of NFPs and no expression of Ki-67.

Patterns of care and survival of glioblastoma patients: a comparative study between 2004 and 2008 in Lyon, France.

INTRODUCTION: The treatment of glioblastomas (GBMs) has changed significantly since 2005. However, the extent to which this change has improved overall survival (OS) of patients treated outside clinical trials remains to be determined. METHODS: We compared the patterns of care and OS of all GBM patients diagnosed in 2004 (n=105) and in 2008 (n=130) in our center. RESULTS: Younger patients (aged<70 years) diagnosed in 2008 received temozolomide radiochemotherapy as the initial treatment and bevacizumab at recurrence more frequently than those diagnosed in 2004 (69% vs 26% P<10(-4) and 41% vs 3%, P<10(-4), respectively). Elderly patients (aged≥70 years) diagnosed in 2008 received an oncological treatment (radiotherapy and/or chemotherapy) more frequently than those diagnosed in 2004 (67% vs 38%, P=0.006). The patients diagnosed in 2008 had longer OS than those diagnosed in 2004 (10.5 months vs 5.3 months, P=0.001). This finding was true for both younger and elderly patients (15.3 months vs 8.9 months, P=0.02 and 6.4 months vs 3.2 months, P=0.0002, respectively) and when considering only IDH1 wild-type patients (8.9 months vs 5.3 months, P=0.004). CONCLUSION: In our center, the change in the patterns of care for GBMs between 2004 and 2008 has been associated with a significant improvement in OS.

Role of surgery, radiotherapy and chemotherapy in papillary tumors of the pineal region: a multicenter study.

Papillary tumor of the pineal region (PTPR), recently described as a distinct clinicopathological entity, can show aggressive biological behavior. The optimal therapeutic approach of PTPR has not been well defined. The role of surgery, radiotherapy, and chemotherapy in the treatment of PTPR was analyzed in a large multicenter series. In order to determine factors that influence prognosis, outcome data of a series of 44 patients with histopathologically proven PTPR were retrospectively analyzed. Of the 44 patients, 32 were still alive after a median follow-up of 63.1 months. Twelve patients experienced progressive disease, with seven undergoing two relapses and five more than two. Median overall survival (OS) was not achieved. Median progression-free survival (PFS) was 58.1 months. Only gross total resection and younger age were associated with a longer OS, radiotherapy and chemotherapy having no significant impact. PFS was not influenced by gross total resection. Radiotherapy and chemotherapy had no significant effect. This retrospective series confirms the high risk of recurrence in PTPR and emphasizes the importance of gross total resection. However, our data provide no evidence for a role of adjuvant radiotherapy or chemotherapy in the treatment of PTPR.

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 < 0.0001). However, there was no statistically significant difference in either overall or disease-free survival evaluated by the Kaplan-Meier method for patients with different grade tumours or Ki67 LI, possibly due to the different clinical management of patients in different centres. CONCLUSIONS: The Ki67 LI may be a useful additional tool for grading PPTs, more particularly in small tumour samples.

[Medulloblastomas: review]. / Les médulloblastomes: revue générale.

INTRODUCTION: The term of "medulloblastoma" refers to cerebellar tumors belonging to the family of primitive neuro-ectodermic tumors (PNET). Medulloblastomas represent 40% of cerebellar tumors, 15 to 20% of brain tumors and the first cause of malignant brain tumors in childhood. Seventy to 80% of cases are diagnosed in children versus 20 to 30% in adults. UPDATED KNOWLEDGE: Diagnosis is based on clinical and radiological exams, and proved on pathological analysis in association with molecular biology. Treatment comprises surgery, craniospinal radiotherapy except for children under five years of age and chemotherapy according to age and high-risk criteria. Medulloblastoma is a rare case of a central nervous system tumor which is radio- and chemo-sensitive. Treatment goals are, on one hand, to improve the survival rates and, on the other hand, to avoid late neurocognitive, neuroendocrine and orthopedic side effects related to radiation therapy, notably in children. The prognosis is relatively good, with a five year survival rate over 75% after complete resection of a localized tumor although sequelae may still compromise outcome. PERSPECTIVES AND CONCLUSION: Management of patients with medulloblastoma implies a multidisciplinary approach combining the contributions of neurosurgery, neuroradiology, pediatric oncology, neuro-oncology and radiotherapy teams.

Expression of c-Myc, neurofibromatosis Type 2, somatostatin receptor 2 and erb-B2 in human meningiomas: relation to grades or histotypes.

Meningiomas, which originate from arachnoid cells, represent one of the largest subgroups of intracranial tumors. They are generally benign, but can progress to malignancy. The aim of our study was to determine the expression of 4 genes, c-Myc, neurofibromatosis Type 2 (NF2), somatostatin receptor isoform 2 (sst2) and erb-B2, that have been associated with tumorogenesis or, possibly, with aggressive behavior or recurrence of meningiomas. We measured levels of mRNAs coding for these genes by qRT-PCR in 51 cases and levels ofc-Myc protooncogene and sst2 protein by immunohistochemistry in 26 cases of meningiomas of various grades and histotypes. C-Myc mRNA and protein levels were not grade-related, but validated subdivision of the 36 benign meningiomas into two groups, Groups IA and IB, based on histological and clinical features (Ki-67-proliferative index, absence or presence of mitoses, rate of recurrence and incidence of perilesional edema). In addition to histopathological grading, c-Myc expression may be useful in predicting tumor recurrence in patients with low-grade meningiomas. NF2 mRNA levels and sst2 mRNA and receptor levels were not grade-related, but were histotype-related, with significantly higher levels in the meningothelial subtype than in the fibroblastic subtype. Erb-B2 mRNA levels were not grade- or histotype-related. Furthermore, the high expression of sst2 in meningothelial meningioma suggests the possibility of a different tumorigenesis process in this meningioma subtype and may open perspectives for the diagnosis and therapy of this subtype using somatostatin as an antiproliferative agent.

Pathology of tumors of the pineal region.

Tumors of the pineal region are rare and relatively few centers around the world have published substantial numbers of carefully studied cases. This review gives a historical account of our understanding of the normal pineal and the evolution of the classification of tumors and other mass lesions of the pineal region in human beings. Based on our experience over the past 30 years, a working classification is proposed and recent advances in the neuropathology of these lesions are discussed.

Histological features and expression of enzymes implicated in melatonin synthesis in pineal parenchymal tumours and in cultured tumoural pineal cells.

Pineal parenchymal tumours (PPT) are rare neoplasms and there have been few in vitro studies. Their capacity for synthesizing and secreting melatonin has been only partially examined. We investigated the presence of messenger RNA (mRNA) encoding tryptophan hydroxylase (TPH), arylalkylamine N-acetyltransferase (AANAT), hydroxyindol-O-methyltransferase (HIOMT), three enzymes involved in melatonin synthesis, and c-myc, a tumoural marker, in 10 PPT, one papillary tumour of the pineal region (PTPR), cell cultures derived from four PPTs and from three other tumours of the pineal region, and in normal pineal gland. Moreover, protein expression of TPH was investigated in three PPT and PTPR. Quantitative real-time reverse transcriptase-polymerase chain reaction and immunohistochemistry were used and the melatonin production by tumoural cells in vitro was analysed by radioimmunoassay. We showed that all the tumoural tissues and cells contained c-myc mRNA. mRNAs encoding TPH, AANAT and HIOMT were detected in all PPT, suggesting that tumour cells can synthesize melatonin. Only PPT expressed TPH protein. Cultured cells lost expression of transcripts throughout passages even if ultrastructural study revealed the presence of characteristic organelles in these tumoural cells. Nevertheless, the basal secretion of melatonin observed in one PPT culture is in favour of a maintained melatonin production and secretion by tumoural pinealocytes, but melatonin production was not stimulated by a beta noradrenergic agonist. Moreover, PTPR never expressed mRNA encoding TPH, AANAT and HIOMT. Our results may contribute to a better understanding of the biology of PTT and PTPR and may help to the diagnosis of these rare tumours.

Reactive perivascular T-cell infiltrate predicts survival in primary central nervous system B-cell lymphomas.

Well-established histopathological prognostic factors are lacking in primary central nervous system (CNS) lymphomas (PCNSL). The present study investigated the presence and prognostic role of tumour necrosis (TN) and reactive perivascular T-cell infiltrate (RPVI), defined as a rim of small reactive T-lymphocytes occurring alone or located between the vascular wall and large neoplastic cells, in tumour samples from 100 immunocompetent patients with PCNSL. World Health Organization histotypes of the patients were: 96 diffuse large B-cell lymphomas, two Burkitt-like lymphomas, one anaplastic large T-cell lymphoma and one unclassified B-cell lymphoma. TN was observed in 24 (24%) cases and RPVI in 26 (36%) of 73 assessable cases. Patients with RPVI-positive lesions exhibited a significantly better overall survival (OS) than patients with RPVI-negative lymphoma, particularly among patients treated with high-dose methotrexate-based chemotherapy (3-year OS: 59 +/- 14% vs. 42 +/- 9%, P = 0.02). By contrast, the presence of TN did not demonstrate prognostic significance. Multivariate analysis confirmed an independent association between RPVI and survival. In conclusion, the presence of RPVI is independently associated with survival in PCNSL. This parameter can be easily and routinely assessed at diagnosis on histopathological specimens.

[Intracranial ependymomas in adult patients. Retrospective analysis of 121 cases from the multicentric French study]. / Ependymomes intracrâniens de l'adulte. Analyse rétrospective de 121 cas provenant de l'étude multicentrique française.

Ependymomas are rare intracranial tumors observed in adults. Prognostic factors as well as proper therapeutic management remain controversial. We report a retrospective study of 121 cases intracranial ependymomas diagnosed between 1990 and 2004 in adult patients. Mean age was 46 years with a 1/1 sex-ratio. Supratentorial and infratentorial localization was noted for 41 (33.9%) and 80 (66.1%) patients respectively. Total gross resection was achieved for 62.8% of tumors. WHO staging was grade II for 72.7% and III for 27.3%. Recurrence developed in 41 (33.9%) patients. Median follow-up was 70 months. The 5-year and 10-year overall survivals were 85 and 76% respectively; the respective progression-free survivals were 64 and 43%. At univariate analysis, age, KPS, localization, extent of surgery and histological grade were correlated with overall survival. At multivariate analysis age, location, histological grade and extent of surgery contributed most to prediction of overall survival. Concerning progression-free survival, univariate analysis found age, KPS, localization, extent of surgery, complementary treatment and histological grade to be correlated with recurrence. Multivariate analysis retained extent of surgery, histological grade and complementary treatment as the most important predictors of progression-free survival. This study demonstrated that extent of surgery and tumor grade are the two main prognostic factors in adult intracranial ependymomas with respect to overall and progression-free survival. Furthermore, our data suggest that postoperative radiotherapy significantly increases progression-free survival in patients with incompletely resected grade II tumors.

[Intracranial ependymomas in adult patients. Diagnosis and histological prognostic factors]. / Ependymomes intracrâniens de l'adulte. Diagnostic histologique et facteurs histopronostiques.

BACKGROUND: Intracranial ependymomas are rare in adults and histopathological prognostic factors are poorly determined. PURPOSE: A retrospective multicentric study was conducted in France in order to assess the prognostic value of histology. MATERIAL: Between 1990 and 2004, 216 adult patients with newly diagnosed ependymomas were treated in 19 French centers. Eligibility required institutional histopathological confirmation of an ependymoma and available clinical history and MRI features (see comparison paper). METHODS: Histological preparations and one paraffin embedded block from each patient were sent to Pr D. Figarella-Branger in Marseille. Central review by four neuropathologists (D. Figarella-Branger, A. Maues de Paula, C. Fernandez and A. Jouvet) was performed. Specimens for which all pathologists agreed with the histological diagnosis of ependymomas were included, whereas cases for which all disagree were excluded and reclassified. In the event of doubt and/or discrepancies between pathologists immunostaining was performed in order to reach a consensus diagnosis. Diagnostic of ependymomas was confirmed in 121 cases (56%). In theses cases, ependymomas were classified according to the WHO system (subtype and grade). The potential prognostic value (overall survival OS and disease free survival DFS) of the following histological parameters was examined: perivascular pseudorosettes, ependymal rosettes, hyalinized vessels, mitotic index, microvascular proliferation, necrosis, area of increased cellularity, nuclear atypia, brain invasion and Mib-1 labelling index. RESULTS: Among the 121 ependymomas, 88 were grade II (47 classic, 17 cellular, 2 papillar, 6 clear cells and 16 tanicytic) and 33 grade III. WHO grading, occurrence of microvascular proliferation, necrosis, nuclear atypia and high proliferative index were correlated with both OS and DFS. Moreover, quantification of certain parameters enabled a reproducible grading system correlated with both OS and DFS.

[Cerebral amyloid angiopathy]. / L'angiopathie amyloïde cérébrale.

Cerebral amyloid angiopathy (CAA) is characterized by deposition of cerebrovascular amyloid protein in the media of leptomeningeal vessels. (amyloid B protein, cystatin C, transthyretin, gelsolin, and prion protein). It is a cause of cerebrovascular disorders including cerebral hemorrhage, cognitive impairment and unusually transient neurological symptoms. It is the main contributing factor to cerebral hemorrhage after hypertension in the elderly. We aimed to review epidemiological, pathophysiological and clinical and MRI imaging data in CAA.