Brain tumour diagnostics using a DNA methylation-based classifier as a diagnostic support tool.

AIMS: Methylation profiling (MP) is increasingly incorporated in the diagnostic process of central nervous system (CNS) tumours at our centres in The Netherlands and Scandinavia. We aimed to identify the benefits and challenges of MP as a support tool for CNS tumour diagnostics. METHODS: About 502 CNS tumour samples were analysed using (850 k) MP. Profiles were matched with the DKFZ/Heidelberg CNS Tumour Classifier. For each case, the final pathological diagnosis was compared to the diagnosis before MP. RESULTS: In 54.4% (273/502) of all analysed cases, the suggested methylation class (calibrated score ≥0.9) corresponded with the initial pathological diagnosis. The diagnosis of 24.5% of these cases (67/273) was more refined after incorporation of the MP result. In 9.8% of cases (49/502), the MP result led to a new diagnosis, resulting in an altered WHO grade in 71.4% of these cases (35/49). In 1% of cases (5/502), the suggested class based on MP was initially disregarded/interpreted as misleading, but in retrospect, the MP result predicted the right diagnosis for three of these cases. In six cases, the suggested class was interpreted as 'discrepant but noncontributory'. The remaining 33.7% of cases (169/502) had a calibrated score <0.9, including 7.8% (39/502) for which no class indication was given at all (calibrated score <0.3). CONCLUSIONS: MP is a powerful tool to confirm and fine-tune the pathological diagnosis of CNS tumours, and to avoid misdiagnoses. However, it is crucial to interpret the results in the context of clinical, radiological, histopathological and other molecular information.

Rare childhood hybrid histiocytosis of the central nervous system-diagnosed by stereotactic brain biopsy with marked treatment response to clofarabine.

Histiocytosis is a heterogeneous group of disease entities, comprised by two main categories, namely Langerhans and non-Langerhans cell histiocytoses. Central nervous system involvement in histiocytosis is considered very rare and is often secondary to affection of anatomically related bone structures and/or multi-organ disease. We present a never-before described case of rare childhood histiocytosis with hybrid features of Langerhans cell histiocytosis and juvenile xanthogranuloma confined to the central nervous system in a 2- and a half-year-old boy with distinct treatment response to clofarabine. The case also emphasizes the diagnostic significance of stereotactic brain biopsy.

Surgical management of colloid cyst of the third ventricle.

BACKGROUND: The aim of this study of third ventricular colloid cysts (TVCC) from a defined population was to estimate the incidence, the presenting features, the surgical treatment, the treatment related complications, and the clinical and surgical outcomes. METHODS: A reprospective study of 32 consecutive primary surgeries for TVCC was performed at Oslo University Hospital in the time period 2002-2015. RESULTS: The estimated incidence rate for TVCC was 0.9 per million. Mean age was 41 years and the male-to-female ratio was 1:1.5. The most common presenting symptoms were headache (100%), ataxia (25%), reduced level of consciousness (22%), and impaired vision (19%). The surgical mortality was 0%. Gross total resection (GTR) was achieved in 69% based on intraoperative findings and in 81% based on postoperative imaging. The rate of surgery-related complications was 13%. There was no statistically significant difference between microsurgery and endoscopic surgery with respect to surgery-related complications and grade of resection. At time of follow-up, all patients were able to care for themselves. CONCLUSIONS: Due to the risk of acute neurological deterioration and sudden death, surgical treatment is recommended for patients with symptomatic TVCC. This study shows that surgical resection can be performed with a fairly low risk and with a good long-term outcome.

Are melanomas averse to cerebellum? Cerebellar metastases in a surgical series.

OBJECTIVES: To study the propensity of different cancers to metastasize to the cerebrum and cerebellum, and to study overall survival (OS) and prognostic factors for patients after surgical resection for cerebellar metastases. MATERIALS AND METHODS: From a prospectively collected tumor database, all patients that underwent a craniotomy for intracranial metastases between 2003 and 2011 at Oslo University Hospital were included. RESULTS: One hundred and forty patients underwent resection for cerebellar metastases. Most common primary tumor sites were lung, colon/rectum, and breast in 45%, 19%, and 14%, respectively. None were prostate cancers. Melanoma metastases were significantly underrepresented, and colorectal cancer metastases significantly overrepresented in cerebellum, compared to the overall proportion of cerebellar/supratentorial metastases surgically resected (P < 0.05). Thirty-day post-operative mortality rate was 4.3%. Median OS was 7.7 months (95% CI 6.0-9.5 months) irrespective of post-operative adjuvant therapy. Median OS was 51.8, 8.4, and 3.4 months, respectively, for recursive partitioning analysis class 1(n = 11), 2 (n = 78) and 3 (n = 34). Significant negative prognostic factors were age ≥65 years, Karnofsky performance score (KPS) <70, extracranial metastases and uncontrolled systemic disease. CONCLUSIONS: Melanoma metastases were significantly underrepresented in cerebellum, whereas colorectal cancer metastases were significantly overrepresented. Surgical mortality and OS after surgical treatment of cerebellar metastases were similar to the results of supratentorial metastases.

Outcome following surgery for intracranial meningiomas in the aging.

OBJECTIVE: To prospectively assess mortality, morbidity and the functional and symptomatic outcome following intracranial surgery for meningiomas in elderly patients at two neurosurgical institutions in Norway. METHODS: Patients ≥60 years who underwent craniotomies for intracranial meningiomas at Oslo University Hospital and Haukeland University Hospital in 2008 and 2009 were included (n = 54). Outcome was assessed at 6 months. RESULTS: Thirty-five females and 19 males of median age 70 (60-84) years were assessed pre- and post-operatively, 87% attended follow-up at 6 months. The surgical mortality rate was 5.6% at 30 days and 7.4% at 3 and 6 months. The rates of complications were: post-operative hematomas 5.6%, deep venous thrombosis 1.9%, osteitis 1.9%, cerebrospinal fluid disturbances 13.0% and neurological sequelae 13.0%. Surgery resulted in a significant improvement in the MMSE score, with a further 14.9% obtaining scores of ≥25 without a significant change in the level of independence according to the Karnofsky performance scale. QoL assessments showed good functioning post-operatively compared to other cancer patient groups, yet slightly reduced when compared to data from the general population. CONCLUSION: In our series, we found that meningioma surgery in the aging patient carries a higher risk of mortality and morbidity compared to intracranial tumor surgery in general. Our findings indicate, however, that the survivors have improved cognitive function and acceptable QoL, and we did not see any significant decrease in the proportion of independent patients according to the KPS.

Craniotomy for brain metastases: a consecutive series of 316 patients.

OBJECTIVE: To assess the incidence of craniotomy for brain metastases, overall survival (OS), surgical mortality, and prognostic factors in a large, contemporary, consecutive series from a well-defined catchment area. MATERIAL AND METHODS: All patients ≥ 18 years who underwent craniotomies for intracranial metastases at Oslo University Hospital, Rikshospitalet and Ullevål, between 2005 and June 30, 2009 were included (n = 316). Patients were identified from our prospectively collected database and a thorough review of all charts to validate the entered data was performed. RESULTS: The annual incidence of first-time craniotomy for a brain metastasis was 2.6/100,000 inhabitants. Patient age ranged from 25 to 87 years (median 64 years). The 30-day mortality rate was 3.8%. Median OS was 9.2 months. Recursive partitioning analysis was class I in 19.6%, class II in 59.2%, and class III in 21.2% with median OS of 16.2, 8.9, and 5.6 months, respectively (P < 0.001). Lung cancer and melanoma were associated with a higher risk (>1% per year) of developing brain metastases. Significant negative prognostic factors were age ≥ 65, a poor performance score, unstable extracranial disease, presence of extracranial metastases, multiplicity, metastasis in eloquent area, and no post-operative radiotherapy. CONCLUSIONS: In this population study, the annual incidence of a first-time craniotomy for a brain metastasis was 2.6/100,000, the 30-day mortality rate was 3.8%, and median OS was 9.2 months. The well-known prognostic factors were confirmed.

Molecular cytogenetic analysis of a gliosarcoma with osseous metaplasia.

Gliosarcoma, a rare glioblastoma variant, is composed of a glial and a mesenchymal component. Though the mesenchymal portion most commonly resembles a fibrosarcoma, other differentiation patterns have been observed. We present the first genomic characterisation (karyotyping followed by FISH and array comparative genomic hybridisation analysis) of a gliosarcoma with osseous metaplasia. In addition to chromosomal changes often found in gliomas (+7, -10, -13, and -22), the tumour cells also harboured a hitherto unknown t(3;21)(q13∼21;q21∼22).

Acute postoperative seizures after epilepsy surgery - a long-term outcome predictor?

OBJECTIVES: The prognostic value of acute postoperative seizures (APS) after epilepsy surgery is much debated. This study evaluated APS, defined as seizures in the first week post-surgery, as a predictor of long-term seizure outcome, and investigated the utility of other potential outcome predictors. MATERIALS AND METHODS: Medical records of 48 patients with temporal and extra-temporal epilepsy surgery were studied. Forty patients had lesional surgery. All had at least 2 year postoperative follow-up. RESULTS: At 2 year follow-up, 25 patients (53%) were seizure free. Univariate analysis showed that APS (P = 0.048), using ≥ six AEDs prior to surgery (P = 0.03), pathological postoperative EEG (P = 0.043) and female gender (P = 0.012) were associated with seizure recurrence. CONCLUSIONS: Univariate analysis indicate that APS, a high number of AEDs used prior to surgery, and pathological postoperative EEG are possible predictors of seizure recurrence after epilepsy surgery. Only gender retained significance in the multivariate analysis.

Low frequency of VHL germline mutations in Norwegian patients presenting with isolated central nervous system hemangioblastomas--a population-based study.

OBJECTIVES: Explore the genetic and clinical incidence of von Hippel-Lindau disease in patients presenting with isolated central nervous system hemangioblastomas. RESULTS: We report a 3.2% (1/31) and 25% (8/32) incidence of genetic and clinical VHL, respectively. One patient tested positive for a VHL mutation that has not previously been reported. This genotype phenotypically predicts VHL type 2B. We had seven patients with renal cysts. In a total follow-up of 33 person years, none of these cysts progressed to renal cell carcinoma. CONCLUSION: von Hippel-Lindau disease anchored in germline mutations of the VHL gene is rare in the Norwegian population as opposed to clinical VHL disease, which appears to be relatively common in patients with apparently sporadic hemangioblastomas. There exists insufficient data regarding the natural history of patients with renal cysts, which makes it difficult to include or disregard these lesions as an entity of VHL disease.

Overall survival, prognostic factors, and repeated surgery in a consecutive series of 516 patients with glioblastoma multiforme.

OBJECTIVES: To study overall survival (OS), prognostic factors, and repeated surgery in glioblastoma multiforme (GBM). MATERIAL AND METHODS: Retrospective study of 516 consecutive adult patients who underwent primary surgery for a GBM in year 2003-2008. RESULTS: Median age at primary surgery was 63.7 years (range 18.0-88.0). Median OS was 9.9 months. Age > 60 years, poor preoperative ECOG score, bilateral tumor, biopsy rather than resection, and no temozolomide chemoradiotherapy were negative risk factors. Repeat surgery was performed in 65 patients (13%). Median time between first and second surgery was 7 months. Indications for second surgery were increasing neurological deficits (35.4%), raised ICP (33.8%), asymptomatic but reoperated because of tumor progression verified on MRI (20.0%), and epileptic seizures (11%). Patients who underwent repeated surgery had longer OS; 18.4 months vs 8.6 months (P < 0.001). CONCLUSIONS: OS for adult GBM patients was 9.9 months. Negative prognostic factors were increasing age, poor neurological function, bilateral tumor involvement, biopsy instead of resection, and RT alone compared to temozolomide chemoradiotherapy. Our rate of repeated surgery for GBM was 13% and the main indications for second surgery were raised ICP and increasing neurological deficits. In a carefully selected group of patients, repeat surgery significantly prolongs OS.

Intracranial tumor surgery in patients >70 years of age: is clinical practice worthwhile or futile?

OBJECTIVES: To study survival and functional outcome after intracranial tumor surgery in elderly patients. MATERIALS AND METHODS: This is a retrospective study of 289 consecutive patients of age > or =70 years, who underwent primary surgery (resection or biopsy) in the time period 2003-2007 for an intracranial tumor (87 astrocytomas, 79 meningiomas, 62 brain metastases, 33 pituitary adenomas and 28 other tumors). RESULTS: The surgical mortality was 2.8%. Overall survival at 6 months, 1, 2 and 5 years was 73%, 57%, 46% and 38% respectively. Histology, pre-operative Eastern Cooperative Oncology Group (ECOG) performance score and resection, as opposed to biopsy, were significantly associated with survival. Gender, age and American Association of Anaesthetists (ASA) score were not significantly related to survival. One-year survival after surgery for astrocytoma, meningioma, brain metastases and pituitary adenoma were 24%, 94%, 31% and 96% respectively. More than 85% of the patients who were alive 6 months after surgery had a stable or improved ECOG score compared with their pre-operative score. CONCLUSIONS: Surgery for intracranial tumors in selected elderly patients is worthwhile, not futile. Age alone should not be used as a selection criterion for treatment.

Can morphology predict 1p/19q loss in oligodendroglial tumours?

AIMS: To investigate the relationship between phenotype and genotype in oligodendroglial tumours and evaluate whether 1p/19q status can be reliably predicted from histological findings. METHODS AND RESULTS: Three neuropathologists reviewed the association between 10 histological variables, location and genetic losses at 1p, 19q and 17p13 in 63 oligodendroglial tumours (cohort 1). Based on these findings, a multiple logistic regression model for prediction of 1p/19q status was constructed. The ability of this model to predict 1p/19q status was tested on cohort 2, comprising 20 oligodendroglial tumours. Loss of heterozygosity at 1p, 19q and 17p13 was analysed using polymerase chain reaction. Combined 1p/19q loss and losses at 17p13 were mutually exclusive (P < 0.001). The variable H1a (more or <50% of cells with round, uniform nuclei and perinuclear halos) demonstrated the strongest association with 1p/19q status (odds ratio 11.9, 95% confidence interval 3.6, 39.6, P < 0.001). Calcifications, absence of gemistocytic cells and a non-temporal/non-insular location were also associated. The correct 1p/19q status was predicted in 80% of cases in cohort 2. CONCLUSIONS: There is a strong association between phenotype and genotype in oligodendroglial tumours. However, even when all significant variables are accounted for, perfect prediction (100%) of 1p/19q status cannot be obtained.

Gliosarcoma with liposarcomatous component, bone infiltration and extracranial growth.

Gliosarcoma is a highly malignant brain tumor consisting of both a glioblastoma and a mesenchymal component. The latter typically resembles fibrosarcoma, but differentiation patterns resembling osteosarcoma, chondrosarcoma, angiosarcoma and rhabdomyosarcoma have also been described. Molecular-genetic studies have shown that both glioblastoma and the mesenchymal component share identical cytogenetic abnormalities or mutations, suggesting a monoclonal origin from glial cells. We report an unusual case of gliosarcoma that presented as a large intracerebral tumor with infiltration of the temporal bone and the soft tissues in the infratemporal fossa. Microscopically, the tumor consisted of alternating areas of glioblastoma and fibrosarcoma. Focally, areas ofosteosarcomatous and liposarcomatous differentiation were found. Although gliosarcoma with transcranial penetration is very rare, it should be suspected in case of intracranial tumor with glioblastoma-imaging features, infiltration of bone and extracranial growth. Our case of liposarcomatous differentiation in gliosarcoma--together with another very recently reported similar case--expands the morphologic heterogeneity of this peculiar brain tumor.

Histogram analysis of MR imaging-derived cerebral blood volume maps: combined glioma grading and identification of low-grade oligodendroglial subtypes.

BACKGROUND AND PURPOSE: Inclusion of oligodendroglial tumors may confound the utility of MR based glioma grading. Our aim was, first, to assess retrospectively whether a histogram-analysis method of MR perfusion images may both grade gliomas and differentiate between low-grade oligodendroglial tumors with or without loss of heterozygosity (LOH) on 1p/19q and, second, to assess retrospectively whether low-grade oligodendroglial subtypes can be identified in a population of patients with high-grade and low-grade astrocytic and oligodendroglial tumors. MATERIALS AND METHODS: Fifty-two patients (23 women, 29 men; mean age, 52 years; range, 19-78 years) with histologically confirmed gliomas were imaged by using dynamic susceptibility contrast MR imaging at 1.5T. Relative cerebral blood volume (rCBV) maps were created, and 4 neuroradiologists defined the glioma volumes independently. Averaged over the 4 observers, a histogram-analysis method was used to assess the normalized histogram peak height of the glioma rCBV distributions. RESULTS: Of the 52 patients, 22 had oligodendroglial tumors. The histogram method was able to differentiate high-grade gliomas (HGGs) from low-grade gliomas (LGGs) (Mann-Whitney U test, P < .001) and to identify low-grade oligodendroglial subtypes (P = .009). The corresponding intraclass correlation coefficients were 0.902 and 0.801, respectively. The sensitivity and specificity in terms of differentiating low-grade oligodendroglial tumors without LOH on 1p/19q from the other tumors was 100% (6/6) and 91% (42/46), respectively. CONCLUSION: With histology as a reference, our results suggest that histogram analysis of MR imaging-derived rCBV maps can differentiate HGGs from LGGs as well as low-grade oligodendroglial subtypes with high interobserver agreement. Also, the method was able to identify low-grade oligodendroglial tumors without LOH on 1p/19q in a population of patients with astrocytic and oligodendroglial tumors.

Prenatal diagnosis of tracheal obstruction: possible association with maternal pertussis infection.

A fetus with the sonographic appearance of echogenic and enlarged lungs and dilated trachea and bronchi, indicating laryngotracheal obstruction, is reported. Additionally, the fetus had ascites and subcutaneous edema and the amniotic fluid volume was reduced. Doppler flow investigation of the systemic venous circulation revealed signs of heart failure, and color Doppler visualized possible increased pulmonary flow. Following termination of pregnancy, autopsy confirmed the sonographic observations and revealed a hypoplastic thymus. During the present pregnancy the mother suffered from sustained cough, and serological tests revealed acute pertussis infection. Polymerase chain reaction investigation for Bordetella pertussis in the amniotic fluid was negative. The possibilities of pertussis toxins as noxious factors and of an atypical presentation of DiGeorge anomaly are discussed.

Neurosurgical treatment of meningiomas in children and young adults.

OBJECT: We studied the frequency, functional outcome, association with neurofibromatosis (NF) and relapse in patients operated on for meningiomas at age 0-20 years in three Norwegian centers between 1972 and 1999. METHODS: Information was collected by examining case notes and histology records, conducting telephone interviews and performing new radiological investigations. Twenty-seven patients were identified. Five had NF, and all 5 developed multiple tumors. In non-NF patients, relapse occurred in 2 out of 19 who underwent total tumor resection, and in all 3 whose surgery was non-radical. There was 1 postsurgical death, and no other major complications. Most patients had few complaints or none at all resulting from their previous tumor or treatment. CONCLUSIONS: Meningiomas without NF have a good prognosis in children and young adults if the tumor can be removed radically. However, relapse can occur many years after the primary operation.

Uveal melanomas with optic nerve extension: report of two cases diagnosed by transvitreal biopsy, one of them with a multicentric tumour.

PURPOSE: To report two cases of invasive uveal melanomas, one of which showed multifocality. METHODS: Clinical examination, ultrasonography, colour Doppler analysis, cytological and histopathological evaluations. RESULTS: Transvitreal biopsy (case 1) or fine needle aspiration biopsy (FNAB) (case 2) revealed malignant melanomas in both patients. Light microscopy and immunohistochemical examinations substantiated the diagnosis of mixed cell type melanomas. In addition, one patient had a multifocal melanoma with papilloedema and colour Doppler findings suggestive of optic disc involvement. CONCLUSION: Transvitreal biopsy for histology or cytology is a reliable procedure to obtain an accurate diagnosis without delay of a lesion adjacent to the optic nerve head. In our two cases the biopsy findings led to enucleation.