Molecular and clinical diversity in primary central nervous system lymphoma.

BACKGROUND: Primary central nervous system lymphoma (PCNSL) is a rare and distinct entity within diffuse large B-cell lymphoma presenting with variable response rates probably to underlying molecular heterogeneity. PATIENTS AND METHODS: To identify and characterize PCNSL heterogeneity and facilitate clinical translation, we carried out a comprehensive multi-omic analysis [whole-exome sequencing, RNA sequencing (RNA-seq), methylation sequencing, and clinical features] in a discovery cohort of 147 fresh-frozen (FF) immunocompetent PCNSLs and a validation cohort of formalin-fixed, paraffin-embedded (FFPE) 93 PCNSLs with RNA-seq and clinico-radiological data. RESULTS: Consensus clustering of multi-omic data uncovered concordant classification of four robust, non-overlapping, prognostically significant clusters (CS). The CS1 and CS2 groups presented an immune-cold hypermethylated profile but a distinct clinical behavior. The 'immune-hot' CS4 group, enriched with mutations increasing the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) and nuclear factor-κB activity, had the most favorable clinical outcome, while the heterogeneous-immune CS3 group had the worse prognosis probably due to its association with meningeal infiltration and enriched HIST1H1E mutations. CS1 was characterized by high Polycomb repressive complex 2 activity and CDKN2A/B loss leading to higher proliferation activity. Integrated analysis on proposed targets suggests potential use of immune checkpoint inhibitors/JAK1 inhibitors for CS4, cyclin D-Cdk4,6 plus phosphoinositide 3-kinase (PI3K) inhibitors for CS1, lenalidomide/demethylating drugs for CS2, and enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2) inhibitors for CS3. We developed an algorithm to identify the PCNSL subtypes using RNA-seq data from either FFPE or FF tissue. CONCLUSIONS: The integration of genome-wide data from multi-omic data revealed four molecular patterns in PCNSL with a distinctive prognostic impact that provides a basis for future clinical stratification and subtype-based targeted interventions.

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.

Neuroendoscopic management of posterior third ventricle and pineal region tumors: technique, limitation, and possible complication avoidance.

The endoscopic approach has gained an increased popularity in recent years for the biopsy and, in selected cases, the removal of tumors of the posterior third ventricle and pineal region. The authors report their experience on a series of 20 patients discussing also the technical limitations and complication avoidance. This is a prospective study of 20 patients with posterior third ventricle and pineal region tumors surgically managed by endoscopic biopsy and/or excision and simultaneous third ventriculostomy. The removal of the lesion could be achieved in 12 cases whereas in 8, only a biopsy could be performed. A histological diagnosis could be obtained in all cases. No delayed third ventricular stoma failures were recorded in any patient at the latest follow-up (mean follow-up, 39 months). Severe postoperative complications were recorded in 2 out of 12 cases of tumor removal attempt and in zero out of eight cases of biopsy. A delayed (3 weeks) postoperative mortality occurred in a patient harboring a GBM that developed an intratumoral hematoma 48 h postoperatively, one patient was in a vegetative state. Transient postoperative complications included: nausea and vomiting (five cases) and diplopia (two cases). One patient developed a bilateral ophthalmoplegia that recovered within 6 months due to residual tumor hemorrhage. Higher rate of complications was found in the case of vascularized and/or larger lesions. Endoscopic management of posterior third ventricle lesions may represent an effective option. However, though biopsies remain often a safe procedure, tumor excision should be limited to highly selected cases (cystic, poorly vascularized, and/or smaller than 2.5-cm lesions).

Hyaline astrocytic inclusions in pediatric epilepsy: report of two cases.

Distinctive hyaline inclusion bodies in the cytoplasm of neocortical astrocytes were observed in surgical resection specimens of a frontal epileptic focus, in 2 patients aged 16 and 10 who had suffered intractable partial seizures since the age of 2 years. One case had minimal neurological impairment and no brain malformation on MRI and recovered completely following surgery. The second case had mental retardation and surgery reduced the frequency and generalization of seizures. In both cases, the astrocytic inclusions were strongly eosinophilic, hyaline and refractile. They were PAS negative. Electron microscopy in the first case, confirmed their granular osmiophilic structure. By immunohistochemistry, the inclusions were strongly positive for filamin in the first case, only some were weakly positive in the second case. They also variably expressed other proteins such as alpha-B-crystallin, GFAP, S-100 protein and cytoglobin. We compare our findings with previously reported cases and discuss the clinical significance of the inclusions and the pathophysiologic relevance of filamin A and other proteins accumulation in astrocytes.

Comparison of MR-arthrography and CT-arthrography in hyaline cartilage-thickness measurement in radiographically normal cadaver hips with anatomy as gold standard.

OBJECTIVE: To compare magnetic resonance (MR)-arthrography and multidetector-spiral-computed-tomography (MDSCT)-arthrography in cartilage-thickness measurement, in hips without cartilage loss, with coronal anatomic slices as gold standard. METHOD: Institutional review board permission to study cadavers of individuals who willed their bodies to science was obtained. Two independent observers measured femoral and acetabular cartilage thicknesses of 12 radiographically normal hips (six women, five men; age range, 52-98 years; mean age, 76.5 years), on MDSCT-arthrographic and MR-arthrographic reformations, and on coronal anatomic slices, excluding regions of cartilage loss. Inter- and intraobserver reproducibilities were determined. Analysis of variance (ANOVA) was used to test differences between MR-arthrographic and MDSCT-arthrographic measurement errors compared to anatomy. RESULTS: By MR-arthrography, cartilage was not measurable at approximately 50% of points on sagittal and transverse sections, compared to 0-6% of the points by MDSCT-arthrography. In the coronal plane, the difference between MDSCT-arthrographic and MR-arthrographic measurement errors was not significant (P=0.93). CONCLUSION: In the coronal plane, MR-arthrography and MDSCT-arthrography were similarly accurate for measuring hip cartilage thickness.

Multifocal Epstein-Barr virus-associated smooth muscle tumor in adults with AIDS: case report and review of the literature.

OBJECTIVES: The aim of this study was to provide a systematic review of Epstein-Barr virus-associated smooth muscle tumors (EBV-SMT) in human immunodeficiency virus (HIV)-infected adults, focusing on clinical and histopathologic features and outcome. METHODS: A literature search was performed using Medline, Embase and the Cochrane Library. RESULTS: We reviewed 35 cases including our case of a patient with a progressive multifocal EBV-SMT. Patients were mainly men (n = 24) with a mean age of 35.5 years. Median CD4 count was 21/mm(3). Main locations were brain (n = 12), liver (n = 8), spinal cord (n = 7) and adrenal gland (n = 6). The tumors were multifocal in 34% of cases, whereas analysis of clonality showed different clones in tumors from different sites. Treatment included removal surgery in 17 cases and/or radiotherapy in 9 and therapeutic abstention in 4. Mean follow-up after diagnosis was 12.3 months. Nine patients died during this period essentially from opportunistic infection and only 2 from the disease. CONCLUSION: EBV-SMT should be added to the list of virally induced tumors in severely immunocompromised HIV-infected adults. Multifocality of independent tumor clones, especially in liver, brain, spinal cord and adrenal gland, and a slow disease progression seem to be the key features of these tumors, the treatment of which remains poorly defined.

Papillary glioneuronal tumor: not always a benign tumor?

Papillary glioneuronal tumor (PGNT) is a variant of ganglioglioma, characterized by a pseudopapillary structure with a single pseudostratified layer of small, cuboidal, GFAP-positive cells around hyalinized blood vessels. To date, less than 30 cases have been described with a usually benign course. We report two additional cases: a clinically, radiologically and histopathologically typical tumor in a 38-year-old man and an atypical tumor with histopathological features of anaplasia in a 74-year-old woman. The latter tumor showed the classical pseudopapillary pattern with ganglioid cells and some astrocytes between the papillae, but also had changes suggestive of anaplasia including necrosis, capillary endothelial proliferation, mitoses, dedifferentiation with loss of GFAP expression of the cuboidal cells and increased Ki-67 labeling of over 10%. Only one other case with increased proliferative activity in a minigemistocytic component has previously been described. Our cases indicate that PGNT type of ganglioglioma can have a spectrum of anaplastic changes of higher grade.

[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.

[Central nervous system lymphoma revealed by lymphocytic meningitis in a patient with systemic lupus erythematosus: An unusual association]. / Méningite lymphocytaire chez une patiente lupique révélant un lymphome cérébral primitif : une association rare.

INTRODUCTION: We report an unusual observation of central nervous system (CNS) lymphoma in a 60-year-old woman with systemic lupus erythematosus and fatal outcome. OBSERVATION: The patient had systemic erythematosus lupus for 7 years, treated with mycophenolate mofetil and developed lymphocytic meningitis in 2015 associated to the presence of EBV in the cerebrospinal fluid and a necrotic vermis' lesion. Diagnosis of large B-cell lymphoma was histologically confirmed from stereotaxic biopsy, shortly before she died from neurological complications. CONCLUSION: Even though the current association is unusual, lymphocytic meningitis with hypoglycorrachia in patients with systemic lupus erythematosus may reveal CNS lymphoma and diagnosis confirmation requires stereotaxic biopsy in order not to delay specific therapeutic management.

Temozolomide as initial treatment for adults with low-grade oligodendrogliomas or oligoastrocytomas and correlation with chromosome 1p deletions.

PURPOSE: To determine the response rate of low-grade oligodendroglial tumors (LGOT) to temozolomide (TMZ) as initial treatment and to evaluate the predictive value of chromosome 1p deletion on the radiologic response. PATIENTS AND METHODS: Adult patients with pathologically proven LGOT with progressive disease on magnetic resonance imaging (MRI) were eligible for the study. TMZ was administered at the starting dose of 200 mg/m2/d for 5 days, repeated every 28 days. Response was evaluated clinically and by central review of MRIs. Chromosome 1p and 19q deletions were detected by the loss of heterozygosity technique. RESULTS: Sixty consecutive patients were included in the study. At the time of analysis, the median number of TMZ cycles delivered was 11. Clinically, 51% of patients improved, particularly those with uncontrolled epilepsy. The objective radiologic response rate was 31% (17% partial response and 14% minor response), whereas 61% of patients had stable disease and 8% experienced disease progression. The median time to maximum tumor response was 12 months (range, 5 to 20 months). Myelosuppression was the most frequent side effect, with grade 3 to 4 toxicity in 8% of patients. Loss of chromosome 1p was associated with objective tumor response (P < .004). CONCLUSION: TMZ is well tolerated and provides a substantial rate of response in LGOT. Chromosome 1p loss is correlated with radiographic response and could be a helpful marker for guiding therapeutic decision making in LGOT.

Middle ear adenoma. A tumor displaying mucinous and neuroendocrine differentiation.

Middle ear adenoma (MEA) is a distinctive, rare entity that appears to be derived from the lining epithelium of the middle ear mucosa. We report four cases of MEA displaying the typical histologic growth pattern. Two distinct tumor cell immunophenotypes were identified in all cases; the first type exhibited positivity with anti-epithelial membrane antigen and anti-keratin antibodies, and the second type showed immunoreactivity with anti-keratin, anti-vimentin, and anti-neuron-specific enolase antibodies. Ultrastructural studies revealed bidirectional mucinous and neuroendocrine differentiation, demonstrated by the presence of two distinct cell types containing apically located mucous granules and basally concentrated neuroendocrine granules, respectively. The presence of neuroendocrine differentiation was supported by the immunohistochemical detection of vasoactive intestinal polypeptide in the tumor cells in one case and neuron-specific enolase in three cases. These findings suggest that the potential for mixed mucinous/neuroendocrine differentiation described in other endodermally derived tumors also exists in middle ear mucosa. We also believe that the rare lesions diagnosed as primary carcinoid tumors of the middle ear might in fact be MEA with predominant or only neuroendocrine differentiation. The clinical course of our four cases and our review of the pertinent literature confirm the benign nature of MEA and indicate that these tumors should be treated by complete local excision without additional therapy.

Biodegradable starch microspheres for cerebral arterial embolization.

RATIONALE AND OBJECTIVES: Various materials have been used to perform intracerebral and cervical arterial embolization for head and neck tumors and vascular malformations. This preliminary prospective study was designed to analyze the clinical and histopathologic consequences of arterial embolization into the brain using biodegradable starch microspheres. METHODS: A new arterial embolization procedure which ensured the integrity of the common and internal carotid arteries, without modifying the arterial flow, was designed. The procedure allowed for cerebral arterial microembolization in 20 Sprague-Dawley rats. Various amounts of biodegradable starch microspheres (Spherex) were introduced into the brain via the left external carotid artery. RESULTS AND CONCLUSIONS: Clinical and histopathologic results suggested that: 1) consequences of cerebral embolization using biodegradable starch microspheres are related to the amount of material embolized; and 2) Spherex microspheres behave differently from degradable microspheres in the brain. Despite the rapid biodegradability of the material, permanent damage from ischemia to the brain was noted.

Immunohistochemical detection of cell proliferation in gastric carcinomas with the monoclonal antibody Ki-67. A study of 24 cases.

The proliferative activity in 24 gastric carcinomas was determined by an immunohistochemical method using monoclonal antibody Ki-67 (ABC method). Immunostained nuclei were counted by two observers through a Nachet NS 1000 image numeriser. Three grades were defined according to stained nuclei percentage (proliferation index Pi = percentage of cells engaged in cellular cycle outside Go): grade 1 (Pi < 20%); grade 2 (20% < Pi < 40%); grade 3 (Pi > 40%). About 60% of tumours were in grade 1 and 10% in grade 3. No correlations were observed between Pi and the following parameters: histological differentiation; parietal extension; presence or absence of metastasis. These results may be compared to the two other available studies of Ki-67 antibody in gastric cancers. Our study also showed a heterogeneous distribution of immunostained nuclei, within each single tumour and from one tumour to another, which has been noted in one previous study and in a similar one we made on colorectal carcinoma. This heterogeneity is the consequence of the variability of carcinomatous cell proliferative activity; an important biological factor in the evaluation of tumoral process. The proliferative activity in gastric carcinomas provides an estimation of tumour dynamics that might be a prospective criterium for tumoral process evaluation.

Serotonin-producing pancreatic endocrine tumour. Histological, ultrastructural and immunohistochemical study of a case.

Serotonin-producing pancreatic endocrine tumours are rare neoplasms which in most cases exhibit malignant biological behaviour. These tumours, in the majority of the well-documented cases, are composed of argyrophil- and argentaffin-positive cells which contain large pleomorphic neurosecretory granules. In contrast, argyrophilic non-argentaffin pancreatic endocrine tumours with tumour cells containing round neurosecretory granules are exceptional. In this study we describe such a tumour not associated with clinical evidence of carcinoid syndrome in a 60-year-old woman. Histological examination revealed tumour extension in pancreatic lymphatic vessels and veins but no evidence of locoregional or distant metastases. Ten months after surgery the patient showed no recurrence of the disease. Immunohistochemistry revealed cytoplasmic serotonin production in the tumour cells which were negative for anti-gastrin, insulin, glucagon, somatostatin, pancreatic polypeptide (PP), vasoactive intestinal peptide (VIP) and ACTH. This study emphasizes the usefulness of combined ultrastructural and immunohistochemical investigations in order to identify and characterize the rare pancreatic endocrine tumours with serotonin production.

MR manifestations of subependymomas.

PURPOSE: To provide a description of the MR and enhanced MR appearances of subependymomas. METHODS: We reviewed the MR examinations of eight cases of pathologically proved subependymomas and correlated them with operative and pathologic reports, and also reviewed the previous published cases of subependymomas documented by MR. Gadopentetate dimeglumine-enhanced MR examination was performed in seven cases. RESULTS: One patient presented with four subependymomas, two patients had subependymomas of the cervical spine, and the others were intraventricular with no transependymal extension. They were isointense to hypointense relative to normal white matter on T1-weighted images, heterogeneous in five cases. Minimal (n = 1) or no (n = 3) enhancement was noted in four cases, and moderate or marked enhancement was noted in three cases. CONCLUSION: We conclude that even though there is no specific sign of subependymomas, when confronted with a complete intraventricular lesion or with a spinal lesion causing little or no edema which is minimally enhancing or nonenhancing, one must consider the diagnosis of subependymoma.

Watershed cerebral infarcts: retrospective study of 24 cases.

Twenty-four patients presenting an acute stroke with watershed cerebral infarct on CT scan or MRI were included in this retrospective study. Age was 63 +/- 14 years (mean +/- SD), and sex ratio was 2 men for 1 woman. Main clinical features were: in anterior location, lower limb weakness and frontal syndrome with transcortical motor aphasia in left lesions or spatial dyscalculia in right ones; in posterior location, brachiofacial weakness with constant quadranopsia and hypoesthesia, and Gerstmann syndrome in left lesion. There was no distinctive feature for subcortical and multiple infarcts. In bilateral infarcts, there were one pseudobulbar syndrome, and 2 pseudo brainstem syndromes with neuropsychological signs. Aetiologies were severe carotid artery disease in 14 cases, severe cardiopathy in 6, isolated cerebral angiitis in 1, essential thrombocythemia in 1, protein C deficiency with sickle cell disease in 1, and cholesterol emboli in 1 anatomical case. CBF performed in carotid artery occlusions or tight stenoses showed evidence of haemodynamic changes. Microembolic process can be proposed in the case with cholesterol emboli. Preventive treatment is discussed.

Foraminal epidural extra osseous cavernous hemangioma of the cervical spine: a case report.

STUDY DESIGN: A case report of purely epidural foraminal cervical cavernous angioma assessed by magnetic resonance imaging and diagnosed at pathologic study. OBJECTIVE: To illustrate a rare cause of cervical foraminal mass mimicking a schwannoma. SUMMARY OF BACKGROUND DATA: Several cases of epidural cavernous angioma have been reported. A purely epidural cavernous angioma in a cervical foramen has never been reported in the literature. METHOD: A 36-year-old man sought treatment for acute weakness in his right upper limb with radicular distribution. On magnetic resonance images, the lesion appeared as a foraminal mass with no bone invasion or hematic components. It enhanced after intravenous administration of Gadolinium. Pathologic study after surgery showed a typical cavernous angioma. RESULTS: The patient improved slightly after surgery. CONCLUSION: Clinical and radiologic presentation could be confusing in a purely foraminal epidural cervical cavernous hemangioma. Cavernous hemangioma must be known as a differential diagnosis of a foraminal schwannoma. Diagnosis of cavernous angioma is made easily on pathologic examination.

[Chloroquine cardiomyopathy revealed by complete atrio-ventricular block. A case report]. / Cardiomyopathie à la chloroquine révélée par un bloc auriculo-ventriculaire complet. A propos d'une observation.

We describe a rare case of chloroquine cardiomyopathy occurring during long term (7 years) treatment for rheumatoid polyarthritis in a 42 year old woman. There was an isolated acute severe conduction defect, which is particularly rare. Histological study with the electron microscope allowed confirmation of this diagnosis. We report here the secondary cardiological effects of this frequently used synthetic antimalarial.

[The epidemiology of cerebral lymphoma in AIDS]. / Epidémiologie des lymphomes cérébraux du SIDA.

Cerebral lymphomas are one of the complications of AIDS. Their increasing frequency, especially in the last decade, has to be correlated with the incidence of systemic lymphomas and especially central nervous system (CNS) lymphomas in non immuno-compromised patients. CNS involvement is found in 40% of systemic lymphomas. Primary lymphomas have an incidence of 0.4-0.56% in epidemiological studies and 7.6% in post-mortem series. Primary lymphomas are noted in all patients, homosexuals, drug-addicts, children, with a lower rate in the haemophiliacs. Known risk factors are HIV itself Epstein-Barr virus almost constantly demonstrated in tumour cells. Epidemiological studies on cerebral lymphomas must still be completed as, until recently, they were included in the group entitled lymphomas, and risk factors have to be specified with more accuracy.