The fourth edition of the World Health Organization (WHO) classification of tumours of the central nervous system, published in 2007, lists several new entities, including angiocentric glioma, papillary glioneuronal tumour, rosette-forming glioneuronal tumour of the fourth ventricle, papillary tumour of the pineal region, pituicytoma and spindle cell oncocytoma of the adenohypophysis. Histological variants were added if there was evidence of a different age distribution, location, genetic profile or clinical behaviour; these included pilomyxoid astrocytoma, anaplastic medulloblastoma and medulloblastoma with extensive nodularity. The WHO grading scheme and the sections on genetic profiles were updated and the rhabdoid tumour predisposition syndrome was added to the list of familial tumour syndromes typically involving the nervous system. As in the previous, 2000 edition of the WHO ‘Blue Book’, the classification is accompanied by a concise commentary on clinico-pathological characteristics of each tumour type. The 2007 WHO classification is based on the consensus of an international Working Group of 25 pathologists and geneticists, as well as contributions from more than 70 international experts overall, and is presented as the standard for the definition of brain tumours to the clinical oncology and cancer research communities world-wide.

https://link.springer.com/content/pdf/10.1007%2Fs00401-007-0243-4.pdf

The 2007 WHO Classification of Tumours of the Central Nervous System

The Central Brain Tumor Registry of the United States (CBTRUS), in collaboration with the Centers for Disease Control (CDC) and National Cancer Institute (NCI), is the largest population-based registry focused exclusively on primary brain and other central nervous system (CNS) tumors in the United States (US) and represents the entire US population. This report contains the most up-to-date population-based data on primary brain tumors (malignant and non-malignant) and supersedes all previous CBTRUS reports in terms of completeness and accuracy. All rates (incidence and mortality) are age-adjusted using the 2000 US standard population and presented per 100,000 population. The average annual age-adjusted incidence rate (AAAIR) of all malignant and non-malignant brain and other CNS tumors was 23.79 (Malignant AAAIR=7.08, non-Malignant AAAIR=16.71). This rate was higher in females compared to males (26.31 versus 21.09), Blacks compared to Whites (23.88 versus 23.83), and non-Hispanics compared to Hispanics (24.23 versus 21.48). The most commonly occurring malignant brain and other CNS tumor was glioblastoma (14.5% of all tumors), and the most common non-malignant tumor was meningioma (38.3% of all tumors). Glioblastoma was more common in males, and meningioma was more common in females. In children and adolescents (age 0-19 years), the incidence rate of all primary brain and other CNS tumors was 6.14. An estimated 83,830 new cases of malignant and non-malignant brain and other CNS tumors are expected to be diagnosed in the US in 2020 (24,970 malignant and 58,860 non-malignant). There were 81,246 deaths attributed to malignant brain and other CNS tumors between 2013 and 2017. This represents an average annual mortality rate of 4.42. The 5-year relative survival rate following diagnosis of a malignant brain and other CNS tumor was 23.5% and for a non-malignant brain and other CNS tumor was 82.4%.

CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2007-2011.

The cancer stem cell (CSC) hypothesis suggests that neoplastic clones are maintained exclusively by a rare fraction of cells with stem cell properties. Although the existence of CSCs in human leukaemia is established, little evidence exists for CSCs in solid tumours, except for breast cancer. Recently, we prospectively isolated a CD133+ cell subpopulation from human brain tumours that exhibited stem cell properties in vitro. However, the true measures of CSCs are their capacity for self renewal and exact recapitulation of the original tumour. Here we report the development of a xenograft assay that identified human brain tumour initiating cells that initiate tumours in vivo. Only the CD133+ brain tumour fraction contains cells that are capable of tumour initiation in NOD-SCID (non-obese diabetic, severe combined immunodeficient) mouse brains. Injection of as few as 100 CD133+ cells produced a tumour that could be serially transplanted and was a phenocopy of the patient's original tumour, whereas injection of 10(5) CD133- cells engrafted but did not cause a tumour. Thus, the identification of brain tumour initiating cells provides insights into human brain tumour pathogenesis, giving strong support for the CSC hypothesis as the basis for many solid tumours, and establishes a previously unidentified cellular target for more effective cancer therapies.

Identification of human brain tumour initiating cells

Over the past decade, comprehensive sequencing efforts have revealed the genomic landscapes of common forms of human cancer. For most cancer types, this landscape consists of a small number of “mountains” (genes altered in a high percentage of tumors) and a much larger number of “hills” (genes altered infrequently). To date, these studies have revealed ~140 genes that, when altered by intragenic mutations, can promote or “drive” tumorigenesis. A typical tumor contains two to eight of these “driver gene” mutations; the remaining mutations are passengers that confer no selective growth advantage. Driver genes can be classified into 12 signaling pathways that regulate three core cellular processes: cell fate, cell survival, and genome maintenance. A better understanding of these pathways is one of the most pressing needs in basic cancer research. Even now, however, our knowledge of cancer genomes is sufficient to guide the development of more effective approaches for reducing cancer morbidity and mortality.

/pdf/cancer-genome-landscapes-qmge4i5y2h.pdf

Cancer Genome Landscapes

background Epigenetic silencing of the MGMT (O 6 -methylguanine–DNA methyltransferase) DNArepair gene by promoter methylation compromises DNA repair and has been associated with longer survival in patients with glioblastoma who receive alkylating agents. methods We tested the relationship between MGMT silencing in the tumor and the survival of patients who were enrolled in a randomized trial comparing radiotherapy alone with radiotherapy combined with concomitant and adjuvant treatment with temozolomide. The methylation status of the MGMT promoter was determined by methylation-specific polymerase-chain-reaction analysis. results The MGMT promoter was methylated in 45 percent of 206 assessable cases. Irrespective of treatment, MGMT promoter methylation was an independent favorable prognostic factor (P<0.001 by the log-rank test; hazard ratio, 0.45; 95 percent confidence interval, 0.32 to 0.61). Among patients whose tumor contained a methylated MGMT promoter, a survival benefit was observed in patients treated with temozolomide and radiotherapy; their median survival was 21.7 months (95 percent confidence interval, 17.4 to 30.4), as compared with 15.3 months (95 percent confidence interval, 13.0 to 20.9) among those who were assigned to only radiotherapy (P=0.007 by the log-rank test). In the absence of methylation of the MGMT promoter, there was a smaller and statistically insignificant difference in survival between the treatment groups. conclusions Patients with glioblastoma containing a methylated MGMT promoter benefited from temozolomide, whereas those who did not have a methylated MGMT promoter did not have such a benefit.

/pdf/mgmt-gene-silencing-and-benefit-from-temozolomide-in-24olu5dmi6.pdf

MGMT Gene Silencing and Benefit from Temozolomide in Glioblastoma

Ollier's disease or multiple enchondromatosis is a deforming dysplastic disease of cartilage involving primarily the metaphyses and diaphyses of long bones It is only rarely associated with sarcomatous degeneration of the enchondromas or other generalized neoplasms A related disease, Maffucci's syndrome, is, however, associated with generalized tumors We present the case of a 29-year-old, albino, black man with Ollier's disease who, as a child, underwent a number of orthopedic procedures for multiple limb deformities and fractures At age 25, he developed hydrocephalus, progressive cranial nerve palsies, and a large enchondroma of the skull base He subsequently underwent multiple shunt procedures and two suboccipital craniectomies Eighteen months later, a brain computed tomographic (CT) scan revealed an intracerebellar mass, which was found to be an anaplastic astrocytoma Two years later, he developed a right hemiparesis and sensory dysfunction with a diffuse supratentorial mass on CT scan A stereotactic biopsy showed this to be a similar anaplastic astrocytoma The literature concerning Ollier's disease is reviewed, and the intracerebral lesions associated with both Ollier's disease and Maffucci's syndrome are examined

A Case of Ollier's Disease Associated with Two Intracranial Gliomas

A microfluorometric analysis was performed to analyse the DNA content of 42 medulloblastomas (MBs) and to seek correlations, if any existed, between the DNA distribution and ploidy values, neoplasm types (i.e. classic vs desmoplastic), histological features of aggressiveness, and immunocytochemical features indicating glial and/or neuronal differentiation. Thirty-one cases were classified as classic and 11 cases as desmoplastic MBs. Ten of 11 desmoplastic MBs had a near-diploid main mode and the remaining 1 case had a near-tetraploid main mode. Moreover, 10 of 11 (90%) cases showed a "monomodal" DNA distribution diagram. All these cases showed a uniform histology. In contrast, classic MBs represented a heterogeneous group of neoplasms. Twenty-two cases were near-diploid, 5 cases were near-tetraploid and 3 cases were near-triploid. The histogram type distribution showed a similar heterogeneity. Twelve of 31 (39%) cases had a monomodal histogram, 12 (39%) cases had a bimodal diagram and 7 (22%) cases a complex DNA distribution. There was a statistically significant difference (P less than 0.001) in terms of prevalence of DNA monomodal histograms between classic and desmoplastic MBs. Significant correlations were not observed among classic MBs between histological features of aggressiveness, type and degree of differentiation and DNA distribution. The present study indicates that desmoplastic MBs represent a homogeneous group of neoplasms in terms of histology and DNA distribution. In contrast, classic MBs are lesions with different degrees of histologically apparent aggressiveness and a complex DNA distribution.

"Desmoplastic" versus "classic" medulloblastoma: Comparison of DNA content, histopathology and differentiation

Magnetic resonance images of 44 patients who had varying degrees of supratentorial signal abnormalities compatible with subcortical arteriosclerotic encephalopathy (SAE) were reviewed for posterior fossa findings. Brain stem lesions frequently accompanied supratentorial SAE and were seen as multiple, fairly symmetric areas of poorly defined, increased signal intensity on axial T2-weighted images. Involvement was generally confined to the central portions of the mid and upper pons. The typical appearance of brain stem involvement by SAE and its probable pathogenesis are reviewed.

Subcortical arteriosclerotic encephalopathy: Brain stem findings with MR imaging

Eighteen patients underwent CT guided stereotactic biopsies using either a Riechert-Mundinger stereotactic frame modified for use in the CT scanner or the CT-based intracranial landmark technique of Gildenberg and a Todd-Wells frame. In seven patients undergoing biopsy with the modified frame technique, representative tissue samples were obtained in all cases. Eleven patients had biopsies using the Gildenberg technique and representative tissue samples were obtained in 10 of the 11. No major postoperative complications occurred in either group. Both techniques allowed samples of intracranial tissue to be obtained safely and efficiently. The modified frame technique provided a higher degree of accuracy while the Gildenberg technique required significantly less CT time and provided a satisfactory degree of accuracy. In seven patients with ring enhancing lesions, biopsies of the enhancing rim provided diagnostic tissue while biopsy of the central low density center of the lesion in three patients provided necrotic material which was useful in histologically grading the tumour.

https://jnnp.bmj.com/content/jnnp/47/6/590.full.pdf

CT-guided stereotactic biopsies using a modified frame and Gildenberg techniques.

Neuritic plaques are prominent in the fascia dentata of the hippocampus and are often linearly oriented in stratum moleculare. Since the afferents to this region are also organized in a laminar pattern, the present study focused on the relative number and laminar distribution of plaques in this region to shed light on the genesis of the neuritic plaques. Examination of 19 brains from patients with Alzheimer's disease showed approximately the same number of plaques in the stratum moleculare of the fascia dentata and in CA1 (Sommer's sector) of the hippocampus, even though the area of the latter is much greater. Laminar analysis of plaque location showed that the plaques were centered on a band between 26% and 40% of the way between the border of stratum granulosum and the outer edge of stratum moleculare. The mean location was 35% of the way through the layer at the intersection of the inner and middle thirds. Plaques appear in approximately the same location, but in lesser numbers, in non-demented patients. The significance of this localization is discussed in terms of the normal anatomy of the fascia dentata and its possible reorganization in Alzheimer's disease. The predictability of plaque formation in this region could be useful in defining the pathogenesis of the neuritic plaque.

Peter C. Burger

Papers

A Case of Ollier's Disease Associated with Two Intracranial Gliomas

"Desmoplastic" versus "classic" medulloblastoma: Comparison of DNA content, histopathology and differentiation

Subcortical arteriosclerotic encephalopathy: Brain stem findings with MR imaging

CT-guided stereotactic biopsies using a modified frame and Gildenberg techniques.

The laminar distribution of neuritic plaques in the fascia dentata of patients with Alzheimer's disease