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.

[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.

[Chordoma]. / Les chordomes.

PURPOSES: To review in the literature, all the epidemiological, clinical, radiological, histological and therapeutic data regarding chordomas as well as various notochordal entities: ecchordosis physaliphora, intradural and intraparenchymatous chordomas, benign notochordal cell tumors, parachordomas and extra-axial chordomas. To identify different types of chordomas, including familial forms, associations with tuberous sclerosis, Ollier's disease and Maffucci's syndrome, forms with metastasis and seeding. To assess the recent data regarding molecular biology and progress in targeted therapy. To compare the different types of radiotherapy, especially protontherapy and their therapeutic effects. To review the largest series of chordomas in their different localizations (skull base, sacrum and mobile spine) from the literature. MATERIALS: The series of 136 chordomas treated and followed up over 20 years (1972-2012) in the department of neurosurgery at Lariboisière hospital is reviewed. It includes: 58 chordomas of the skull base, 47 of the craniocervical junction, 23 of the cervical spine and 8 from the lombosacral region. Similarly, 31 chordomas in children (less than 18 years of age), observed in the departments of neurosurgery of les Enfants-Malades and Lariboisière hospitals, are presented. They were observed between 1976 and 2010 and were located intracranially (n=22 including 13 with cervical extension), 4 at the craniocervical junction level and 5 in the cervical spine. METHODS: In the entire Lariboisière series and in the different groups of localization, different parameters were analyzed: the delay of diagnosis, of follow-up, of occurrence of metastasis, recurrence and death, the number of primary patients and patients referred to us after progression or recurrence and the number of deaths, recurrences and metastases. The influence of the quality of resection (total, subtotal and partial) on the prognosis is also presented. Kaplan-Meier actuarial curves of overall survival and disease free survival were performed in the entire series, including the different groups of localization based on the following 4 parameters: age, primary and secondary patients, quality of resection and protontherapy. In the pediatric series, a similar analysis was carried-out but was limited by the small number of patients in the subgroups. RESULTS: In the Lariboisière series, the mean delay of diagnosis is 10 months and the mean follow-up is 80 months in each group. The delay before recurrence, metastasis and death is always better for the skull base chordomas and worse for those of the craniocervical junction, which have similar results to those of the cervical spine. Similar figures were observed as regards the number of deaths, metastases and recurrences. Quality of resection is the major factor of prognosis with 20.5 % of deaths and 28 % of recurrences after total resection as compared to 52.5 % and 47.5 % after subtotal resection. This is still more obvious in the group of skull base chordomas. Adding protontherapy to a total resection can still improve the results but there is no change after subtotal resection. The actuarial curve of overall survival shows a clear cut in the slope with some chordomas having a fast evolution towards recurrence and death in less than 4 years and others having a long survival of sometimes more than 20 years. Also, age has no influence on the prognosis. In primary patients, disease free survival is better than in secondary patients but not in overall survival. Protontherapy only improves the overall survival in the entire series and in the skull base group. Total resection improves both the overall and disease free survival in each group. Finally, the adjunct of protontherapy after total resection is clearly demonstrated. In the pediatric series, the median follow-up is 5.7 years. Overall survival and disease free survival are respectively 63 % and 54.3 %. Factors of prognosis are the histological type (atypical forms), localization (worse for the cervical spine and better for the clivus) and again it will depend on the quality of resection. CONCLUSIONS: Many different pathologies derived from the notochord can be observed: some are remnants, some may be precursors of chordomas and some have similar features but are probably not genuine chordomas. To-day, immuno-histological studies should permit to differentiate them from real chordomas. Improving knowledge of molecular biology raises hopes for complementary treatments but to date the quality of surgical resection is still the main factor of prognosis. Complementary protontherapy seems useful, especially in skull base chordomas, which have better overall results than those of the craniocervical junction and of the cervical spine. However, we are still lacking an intrinsic marker of evolution to differentiate the slow growing chordomas with an indolent evolution from aggressive types leading rapidly to recurrence and death on which more aggressive treatments should be applied.

Diagnosis of follicular lesions of undetermined significance in fine-needle aspirations of thyroid nodules.

Aim. We aimed to analyze the diagnostic criteria proposed by the Bethesda System for Reporting Thyroid Cytopathology for follicular lesions of undetermined significance (FLUS), the risk of cancer and diagnostic improvement with use of immunocytochemistry. Methods. For each FLUS diagnosis, we analyzed the cytological criteria (9 Bethesda criteria), secondary fine-needle aspiration (FNA) results, surgical procedures, contribution of immunocytochemistry with the antibodies cytokeratin 19 (CK19) and monoclonal anti-human mesothelial cell (HBME1). Results. Among patients with 2,210 thyroid FNAs, 244 lesions (337 nodules) were classified as FLUS (11% of all thyroid FNAs). The 3 criteria most often applied were cytological atypia suggesting papillary carcinoma (36%), microfollicular architecture but sparse cellularity (23.1%), cytological atypia (21.5%). With secondary FNA, 48.8% of nodules were reclassified as benign. For about half of all cases (41.4% for the first FNA, 57.6% for the second FNA), immunocytochemistry helped establishing a diagnosis favoring malignant or benign. No benign immunocytochemistry results were associated with a malignant lesion. In all, 22.5% of the 39 removed nodules were malignant. Conclusion. The FLUS category is supported by well-described criteria. The risk of malignancy in our series was 22.5%. Because we had no false-negative immunocytochemistry results, immunocytochemistry could be helpful in FLUS management.

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).

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.

Dorsal epidural spinal lipomatosis.

The authors report a case of a thoracic epidural spinal lipomatosis causing severe neurological deficits along the review of pertinent literature. The patient is a 56-year-old woman who presented with acute onset of severe paraparesis; she was investigated with cervical and thoracic MRI and then surgically managed because of an intraspinal mass compressing the cord. The operation consisted in the excision of the mass confirmed to be a fibrolipoma by pathological analysis. The patient attained complete neurological recovery and at 18 months follow-up she reported a generalised well-being. Thoracic lipomas are rare lesions that presenting mostly with back pain; however, in rare instances they may cause progressive and/or abrupt neurological dysfunction. Appropriate imaging can help in the diagnosis and management of such cases.

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.

Temozolomide for low-grade gliomas: predictive impact of 1p/19q loss on response and outcome.

OBJECTIVE: To evaluate the predictive impact of chromosome 1p/19q deletions on the response and outcome of progressive low-grade gliomas (LGG) treated with up-front temozolomide (TMZ) chemotherapy. METHODS: Adult patients with measurable, progressive LGG (WHO grade II) treated with TMZ delivered at the conventional schedule (200 mg/m(2)/day for 5 consecutive days, repeated every 28 days) were retrospectively evaluated for response by central review of MRI-s. Chromosome 1p and 19q deletions were detected by the loss of the heterozygosity technique (LOH). RESULTS: A total of 149 consecutive patients were included in this retrospective, single center observational study. The median number of TMZ cycles delivered was 14 (range 2 to 30). Seventy-seven patients (53%) experienced an objective response (including 22 [15%] cases of partial response and 55 [38%] cases of minor response), 55 (37%) patients had stable disease, and 14 (10%) had a progressive disease. The median time to maximum tumor response was 12 months (range 3 to 30 months). The median progression-free survival (PFS) was 28 months (95% CI: 23.4 to 32.6). Material for genotyping was available for 86 patients. Combined 1p/19q LOH was present in 42% of the cases and was significantly associated with a higher rate (p = 0.02) and longer objective response to chemotherapy (p = 0.017), and both longer PFS (p = 4.10(-5)) and overall survival (p = 0.04). CONCLUSION: Low-grade gliomas respond to temozolomide and loss of chromosome 1p/19q predicts both a durable chemosensitivity and a favorable outcome.

[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.

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.

Temporal artery biopsy for diagnosing giant cell arteritis: the longer, the better?

OBJECTIVE: To investigate the relation between temporal artery biopsy (TAB) length and diagnostic sensitivity for giant cell arteritis. METHODS: Histological TAB reports generated from four hospital pathology departments were reviewed for demographics, histological findings, and formalin fixed TAB lengths. A biopsy was considered positive for giant cell arteritis if there was a mononuclear cell infiltrate predominating at the media-intima junction or in the media. RESULTS: Among 1821 TAB reports reviewed, 287 (15.8%) were excluded because of missing data, sampling errors, or age < 50 years. Mean TAB length of the 1520 datasets finally analysed (67.2% women; mean (SD) age, 73.1 (10.0) years) was 1.33 (0.73) cm. Histological evidence of giant cell arteritis was found in 223 specimens (14.7%), among which 164 (73.5%) contained giant cells. Statistical analyses, including piecewise logistic regression, identified 0.5 cm as the TAB length change point for diagnostic sensitivity. Compared with TAB length of < 0.5 cm, the respective odds ratios for positive TAB without and with multinucleated giant cells in samples > or = 0.5 cm long were 5.7 (95% confidence interval, 1.4 to 23.6) and 4.0 (0.97 to 16.5). CONCLUSIONS: A fixed TAB length of at least 0.5 cm could be sufficient to make a histological diagnosis of giant cell arteritis.

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.