Peter C. Burger

The 2007 WHO classification of tumours of the central nervous system.

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.

5' CpG island methylation is associated with transcriptional silencing of the tumour suppressor p16/CDKN2/MTS1 in human cancers.

Loss of heterozygosity on chromosome 9p21 is one of the most frequent genetic alterations identified in human cancer. The rate of point mutations of p16, a candidate suppressor gene of this area, is low in most primary tumours with allelic loss of 9p21. Monosomic cell lines with structurally unaltered p16 show methylation of the 5′ CpG island of p16. This distinct methylation pattern was associated with a complete transcriptional block that was reversible upon treatment with 5-deoxyazacytidine. Moreover, de novo methylation of the 5′ CpG island of p16 was also found in approximately 20% of different primary neoplasms, but not in normal tissues, potentially representing a common pathway of tumour suppressor gene inactivation in human cancers.

The New WHO Classification of Brain Tumours

The new edition of the World Health Organization (WHO) book on ‘Histological Typing of Tumours of the Central Nervous System’ reflects the progress in brain tumour classification which has been achieved since publication of the first edition in 1979. Several new tumour entities have been added, including the pleomorphic xanthoastrocytoma, central neurocytoma, the infantile desmoplastic astrocytoma/ganglioglioma, and the dysembryoplastic neuroepithelial tumour. The list of histological variants has also been expanded. In line with recent morphological and molecular data on glioma progression, the glioblastoma is now grouped together with astrocytic tumours. The classification of childhood tumours has been largely retained, the diagnosis primitive neuroectodermal tumour (PNET) only being recommended as a generic term for cerebellar meduiloblastomas and neoplasms that are histologically indistinguishable from medulloblastoma but located in the CNS at sites other than the cerebellum. The WHO grading scheme was revised and adapted to new entities but its use, as before, remains optional.

Central Nervous System

A construction worker falls from a scaffold that was positioned at the second-story level of a building. He has a severe closed heal injury with a Glasgow Coma Scale of 6. Admission computed tomography (CT) scan demonstrates diffuse axonal injury. No other injuries were found on secondary evaluation and CT evaluation of the cervical spine, chest, and abdomen. Which of the following is the preferred management for this patient? (A) Forced diuresis (B) Barbiturate administration (C) Hyperventilation (72 hours) (D) Craniotomy (E) Intracranial pressure monitoring

The molecular basis of Turcot's syndrome

BACKGROUND Turcots syndrome is characterized clinically by the concurrence of a primary brain tumor and multiple colorectal adenomas. We attempted to define the syndrome at the molecular level. METHODS Fourteen families with Turcots syndrome identified in two registries and the family originally described by Turcot and colleagues were studied. Germ-line mutations in the adenomatous polyposis coli (APC) gene characteristic of familial adenomatous polyposis were evaluated, as well as DNA replication errors and germline mutations in nucleotide mismatch-repair genes characteristic of hereditary nonpolyposis colorectal cancer. In addition, a formal risk analysis for brain tumors in familial adenomatous polyposis was performed with a registry data base. RESULTS Genetic abnormalities were identified in 13 of the 14 registry families. Germ-line APC mutations were detected in 10. The predominant brain tumor in these 10 families was medulloblastoma (11 of 14 patients, or 79 percent), and the relative risk of cerebellar medulloblastoma in patients with familial adenomatous polyposis was 92 times that in the general population (95 percent confidence interval, 29 to 269; P < 0.001). In contrast, the type of brain tumor in the other four families was glioblastoma multiforme. The glioblastomas and colorectal tumors in three of these families and in the original family studied by Turcot had replication errors characteristic of hereditary nonpolyposis colorectal cancer. In addition, germ-line mutations in the mismatch-repair genes hMLH1 or hPMS2 were found in two families. CONCLUSIONS The association between brain tumors and multiple colorectal adenomas can result from two distinct types of germ-line defects: mutation of the APC gene or mutation of a mismatch-repair gene. Molecular diagnosis may contribute to the appropriate care of affected patients.

Alterations of chromosome arms 1p and 19q as predictors of survival in oligodendrogliomas, astrocytomas, and mixed oligoastrocytomas

PURPOSE A recent report suggests that alterations of chromosome arms 1p and 19q are associated with chemotherapeutic response and overall survival in anaplastic oligodendroglioma patients treated with procarbazine, lomustine, and vincristine chemotherapy. We set out to further clarify the diagnostic and prognostic implications of these alterations in a broader set of diffuse gliomas, including astrocytic neoplasms and low-grade oligodendrogliomas. PATIENTS AND METHODS Fluorescence in situ hybridization (FISH) signals from DNA probes mapping to 1p and 19q common deletion regions were enumerated in 162 diffuse gliomas (79 astrocytomas, 52 oligodendrogliomas, and 31 mixed oligoastrocytomas), collected as part of an ongoing prospective investigation of CNS tumors. RESULTS The oligodendroglial phenotype was highly associated with loss of 1p (P =.0002), loss of 19q (P <.0001), and combined loss of 1p and 19q (P <.0001). Combined loss of 1p and 19q was identified as a univariate predictor of prolonged overall survival among patients with pure oligodendroglioma (log-rank, P =.03) and remained a significant predictor after adjusting for the effects of patient age and tumor grade (P <.01). This favorable association was not evident in patients with astrocytoma or mixed oligoastrocytoma. CONCLUSION Combined loss of 1p and 19q is a statistically significant predictor of prolonged survival in patients with pure oligodendroglioma, independent of tumor grade. Given the lack of this association in patients with astrocytic neoplasms and the previously demonstrated chemosensitivity of oligodendrogliomas, a combined approach of histologic and genotypic assessment could potentially improve existing strategies for patient stratification and management.

Postoperative chemotherapy and delayed radiation in children less than three years of age with malignant brain tumors

BACKGROUND Among patients with malignant brain tumors, infants and very young children have the worst prognosis and the most severe treatment-related neurotoxic effects. Therefore, in 1986, the Pediatric Oncology Group began a study in which postoperative chemotherapy was given in order to permit a delay in the delivery of radiation to the developing brain. METHODS Children under 36 months of age with biopsy-proved malignant brain tumors were treated postoperatively with two 28-day cycles of cyclophosphamide plus vincristine, followed by one 28-day cycle of cisplatin plus etoposide. This sequence was repeated until the disease progressed or for two years in 132 children 24 months of age at diagnosis and for one year in 66 children 24 to 36 months of age at diagnosis. After this, the patients received radiation therapy. The response to the first two cycles of chemotherapy was measured in 102 patients with residual postoperative disease. RESULTS The first two cycles of cyclophosphamide and vincristine produced complete or partial responses in 39 percent of the 102 patients who could be evaluated. The response rates were highest among patients with medulloblastomas, malignant gliomas, or ependymomas. Patients with brain-stem gliomas or embryonal tumors (primitive neuroectodermal tumors) had little or no response. The progression-free survival rate was 41 percent at one year for children who were 24 to 36 months old at diagnosis and 39 percent at two years for those under 24 months of age at diagnosis. Multivariate analysis identified embryonal tumors as a significant adverse prognostic feature (relative risk, 2.2; 95 percent confidence interval, 1.4 to 3.4) and complete resection as a favorable feature (relative risk, 0.33; 95 percent confidence interval, 0.20 to 0.54). Complete responses to chemotherapy were associated with a progression-free survival rate approaching that achieved with gross total resection. A comparison of cognitive evaluations obtained at base line and after one year of chemotherapy revealed no evidence of deterioration in cognitive function. CONCLUSIONS Chemotherapy appears to be an effective primary postoperative treatment for many malignant brain tumors in young children. Disease control for one or two years in a large minority of patients permitted a delay in the delivery of radiation and, on the basis of preliminary results, a reduction in neurotoxicity. For patients who had undergone total surgical resection or who had a complete response to chemotherapy, the results are sufficiently encouraging to suggest that radiation therapy may not be needed in this subgroup of children after at least one year of chemotherapy.

Glioblastoma multiforme and anaplastic astrocytoma: Pathologic criteria and prognostic implications

A total of 1440 malignant astrocytic gliomas from three Phase III trials of the National Brain Tumor Study Group were studied to document the clinical usefulness of subclassifying these lesions as either an anaplastic astrocytoma or a glioblastoma multiforme. As defined by a previous “blind” pathology review, the two groups of patients were compared as to mean age, mean duration of preoperative symptoms, and postrandomization survival. In addition, 10 histologic variables were studied in 150 patients with the anaplastic astrocytoma to establish internal correlations, and to relate specific histologic variables to patient age and postrandomization survival. There were highly significant differences in the age, duration of preoperative symptoms, and post randomization survival between the two groups. Internal correlations between histologic variables in the anaplastic astrocytoma disclosed statistically significant associations between the presence of lymphocytes and gemistocytic astrocytes. It is concluded that the subclassification of malignant gliomas into the anaplastic astrocytoma and the glioblastoma multiforme defines groups of patients that are significantly different in regard to age, duration of symptoms, and length of survival. The problems of tissue sampling are recognized, however, the assignment, by a blind pathology review, to two such different groups indicates that the classification has utility for large randomized clinical trials. The analysis of histologic variables in the anaplastic astrocytomas confirms previous suggestions that lymphocytes and gemistocytes frequently coexist in malignant gliomas, but in this study these inflammatory cells did not appear to influence survival. The study reemphasizes the association between advancing age and shorter survivals in patients with malignant gliomas.

Phase III Study of Craniospinal Radiation Therapy Followed by Adjuvant Chemotherapy for Newly Diagnosed Average-Risk Medulloblastoma

PURPOSE To determine the event-free survival (EFS) and overall survival of children with average-risk medulloblastoma and treated with reduced-dose craniospinal radiotherapy (CSRT) and one of two postradiotherapy chemotherapies. METHODS Four hundred twenty-one patients between 3 years and 21 years of age with nondisseminated medulloblastoma (MB) were prospectively randomly assigned to treatment with 23.4 Gy of CSRT, 55.8 Gy of posterior fossa RT, plus one of two adjuvant chemotherapy regimens: lomustine (CCNU), cisplatin, and vincristine; or cyclophosphamide, cisplatin, and vincristine. Results Forty-two of 421 patients enrolled were excluded from analysis. Sixty-six of the remaining 379 patients had incompletely assessable postoperative studies. Five-year EFS and survival for the cohort of 379 patients was 81% +/- 2.1% and 86% +/- 9%, respectively (median follow-up over 5 years). EFS was unaffected by sex, race, age, treatment regimen, brainstem involvement, or excessive anaplasia. EFS was detrimentally affected by neuroradiographic unassessability. Patients with areas of frank dissemination had a 5-year EFS of 36% +/- 15%. Sixty-seven percent of progressions had some component of dissemination. There were seven second malignancies. Infections occurred more frequently on the cyclophosphamide arm and electrolyte abnormalities were more common on the CCNU regimen. CONCLUSION This study discloses an encouraging EFS rate for children with nondisseminated MB treated with reduced-dose craniospinal radiation and chemotherapy. Additional, careful, step-wise reductions in CSRT in adequately staged patients may be possible.

Increasing incidence of primary brain lymphoma in the US

There have been a number of clinical reports suggesting an increasing incidence of primary brain lymphoma unrelated to acquired immune deficiency syndrome (AIDS) and organ transplantation. To investigate this issue, the US incidence of this rare lymphoma was assessed using data from the National Cancer Institutes Surveillance, Epidemiology and End Results (SEER) program (1973 through 1984). Never‐married men, a relatively high risk group for AIDS, were excluded from the analyses. Brain lymphoma incidence increased from 2.7 in 1973 through 1975 to 7.5 cases per ten million population in 1982 through 1984 (chi‐square trend, 15.25; P < 0.001), and it increased among both men (chi‐square trend, 6.74; P = 0.009) and women (chi‐square trend, 10.48; P = 0.001). Increases in incidence also were observed among persons younger than 60 years of age (chi‐square trend, 4.10; P = 0.04) and persons 60 years of age and older (chi‐square trend, 9.16; P = 0.002). This increased incidence of brain lymphoma appears to be real: It antedates the AIDS epidemic and does not appear to be related to organ transplantation, another cause of increased risk of brain lymphoma. Although part of the increase may be an artifact of improvements in diagnostic technology and practice, most of the observed increase antedates the widespread use of such technologies. Finally, the increase in incidence of brain lymphoma does not appear to be related to overall trends in the incidence of brain tumors and non‐Hodgkins lymphoma, and it is not related to time trends in nosology.