David W. Ellison

International Society of Neuropathology‐Haarlem Consensus Guidelines for Nervous System Tumor Classification and Grading

Major discoveries in the biology of nervous system tumors have raised the question of how non‐histological data such as molecular information can be incorporated into the next World Health Organization (WHO) classification of central nervous system tumors. To address this question, a meeting of neuropathologists with expertise in molecular diagnosis was held in Haarlem, the Netherlands, under the sponsorship of the International Society of Neuropathology (ISN). Prior to the meeting, participants solicited input from clinical colleagues in diverse neuro‐oncological specialties. The present “white paper” catalogs the recommendations of the meeting, at which a consensus was reached that incorporation of molecular information into the next WHO classification should follow a set of provided “ISN‐Haarlem” guidelines. Salient recommendations include that (i) diagnostic entities should be defined as narrowly as possible to optimize interobserver reproducibility, clinicopathological predictions and therapeutic planning; (ii) diagnoses should be “layered” with histologic classification, WHO grade and molecular information listed below an “integrated diagnosis”; (iii) determinations should be made for each tumor entity as to whether molecular information is required, suggested or not needed for its definition; (iv) some pediatric entities should be separated from their adult counterparts; (v) input for guiding decisions regarding tumor classification should be solicited from experts in complementary disciplines of neuro‐oncology; and (iv) entity‐specific molecular testing and reporting formats should be followed in diagnostic reports. It is hoped that these guidelines will facilitate the forthcoming update of the fourth edition of the WHO classification of central nervous system tumors.

Management of choroid plexus tumours in children : 20 years experience at a Single Neurosurgical Centre

Objective: Tumours of the choroid plexus are rare tumours of neuro-ectodermal origin, accounting for less than 1% of all intracranial tumours. Most cases present in children less than 2 years of age. While choroid plexus carcinomas (CPC) are reported to have an extremely poor prognosis, choroid plexus papillomas (CPP) are generally regarded as benign tumours with a very favourable long-term outcome. Management dilemmas are associated with the choice of surgical procedure, tumour vascularity, the treatment of hydrocephalus and the value of adjuvant therapy. The objective of this study was to review our experience with this rare tumour over a 20-year period. Methods: Patients were identified from the Great Ormond Street Neurosurgical Brain Tumour Database. Over a 20-year period (1979–1999), 34 children were identified with a choroid plexus tumour. There were 25 cases of CPP and 9 cases of CPC. A retrospective review of case notes, radiological imaging, operation reports and pathology was performed. Results: The median age at presentation was 17 months (1–138) for CPP and 13 months (2–102) for CPC. There was no sex difference for CPP. However, 8 of the 9 CPCs were male (89%). A complete surgical resection was achieved in all 25 cases of CPP and in 3 cases of CPC (33%). The median survival for CPPs was 75.5 months (2–228), with a median follow-up of 73.5 months (2–228). The median survival for CPCs was 6 months (1–90), with a median follow-up of 6 months (1–90). Conclusion: With modern neurosurgical practise, a cure should be the aim for all children with CPP. There is no evidence that adjuvant therapy has any role in the primary management of these children. However, CPC still has an extremely poor prognosis, and the efficacy of adjuvant therapy remains to be established.

Phosphoethanolamine and ethanolamine are decreased in Alzheimer's disease and Huntington's disease

Measurements of both phosphoethanolamine (PEA) and ethanolamine (EA) were made in postmortem brain samples from patients with Alzheimers disease (AD) and Huntingtons disease (HD) using high-performance liquid chromatography with electrochemical detection. In AD levels of PEA were significantly reduced by 64% in temporal cortex, 48% in frontal cortex and 40% in hippocampus. In HD concentrations of PEA were significantly reduced by 76% in the caudate, 53% in putamen and 48% in the nucleus accumbens. EA concentrations showed similar but smaller reductions in both diseases. Both PEA and EA are involved in phospholipid metabolism and can be released with depolarizing stimuli in some circumstances. Since two diverse neuropathologic processes can result in depleted levels of both amines in their respective regions of pathologic predilection, it is likely that the depletions accompany neuronal death.

Amino acid neurotransmitters in postmortem human brain analyzed by high performance liquid chromatography with electrochemical detection

In the present study we have developed a method of measuring putative neurotransmitter amino acids using high performance liquid chromatography (HPLC) with electrochemical detection. The assay had a sensitivity in the low pmol range and sample turnover time was 30 min. The postmortem stability of amino acids was examined in an animal model simulating human autopsy conditions. Aspartate concentrations increased 15% between 4 and 24 h postmortem while gamma-aminobutyric acid (GABA) concentrations rose 35% by 4 h but were stable thereafter. Glutamate and taurine were stable at all time points. The assay has been used to examine concentrations of neurotransmitter amino acids in 15 patients without neurological or psychiatric disease. Results agree well with previous work and knowledge of amino acid neurotransmitter pathways. The current technique provides a reliable method for the study of amino acid transmitter abnormalities in neurological illness.

The effect of neuropeptide Y on striatal catecholamines

Neuropeptide Y and peptide YY were injected into rat striatum and their effects on dopamine, serotonin and their metabolites were examined at 1 h. Neuropeptide Y induced a dose-dependent increase in dopamine turnover in the ipsilateral striatum with no effect on serotonin turnover. When neuropeptide Y was coinjected with somatostatin there was an additive effect in increasing dopamine turnover. There was no alteration in striatal concentrations of gamma-aminobutyric acid, glutamate, or aspartate with either neuropeptide Y or somatostatin injections. These results suggest that neuropeptide Y may play a role with somatostatin in regulating striatal dopaminergic transmission.

Accumulation of p53 and Ki-67 Expression Do Not Predict Survival in Patients with Fibrillary Astrocytomas or the Response of These Tumors to Radiotherapy

OBJECTIVE Although radiotherapy is often used in the treatment of patients with low-grade astrocytomas, its value is still uncertain. Radiotherapy carries a risk of morbidity for patients and has time and cost implications for health services. We have assessed the value of two histological variables, p53 accumulation and Ki-67 expression, in predicting the response of astrocytomas to radiotherapy. The former antigen was assessed because many astrocytic tumors show mutations in the p53 gene, the function of which is crucial for mediating cell death after radiotherapy, and the latter was assessed because it is expressed only in proliferating tumor cells, which may show greater radiosensitivity than nonproliferating cells. METHODS Immunohistochemistry was used to detect the accumulation of p53 and expression of Ki-67 in a retrospective series of 96 patients with supratentorial fibrillary astrocytomas, 58 of whom had received postoperative radiotherapy. The immunohistochemical data were correlated with survival after radiotherapy. RESULTS There was no significant difference in survival between the patients who did and those who did not receive radiotherapy. The p53 and Ki-67 labeling indices did not correlate with survival in either the irradiated or the nonirradiated cohort, nor with overall survival in the series as a whole. CONCLUSION Immunohistochemical assessment of p53 accumulation and Ki-67 expression does not help in predicting the survival of patients with supratentorial fibrillary astrocytomas or in predicting whether particular patients are likely to benefit from radiotherapy.

An examination of neuropeptide Y postmortem stability in an animal model simulating human autopsy conditions.

A rabbit antiserum to neuropeptide Y (NPY) was used to develop a radioimmunoassay for measuring NPY in brain tissue. By high-performance liquid chromatography, two peaks of immunoreactivity were detected in human postmortem cortex. A minor peak was seen at the void volume, while the majority of immunoreactivity comigrated with synthetic NPY standards. Using the Spokes-Koch rat model simulating human autopsy conditions, it was shown that cortical, hippocampal and striatal concentrations of NPY-like immunoreactivity are stable for up to 24 h.

A detailed examination of substance P in pathologically graded cases of Huntington's disease

Substance P concentrations have been found to be reduced in the basal ganglia in Huntingtons disease (HD). In order to further examine this finding in the present study we measured substance P-like immunoreactivity (SPLI) in cases of HD which had been graded as to the severity of pathological changes in the striatum. Marked significant reductions of SPLI were found in all striatal nuclei which were significantly correlated with the percentage of neuronal loss in the varying pathologic grades. Similar changes were found in the projection sites of striatal substance P neurons, the globus pallidus interna and the substantia nigra. These changes are consistent with a loss of striatal substance P containing projection neurons in HD. Significant reductions in SPLI were also found in the external pallidum, bed nucleus of the stria terminalis and the subthalamic nucleus. Small significant increases in SPLI (20-30%) were found in 3 frontal cortical regions (Brodmann areas 6, 8 and 9). The finding of neurochemical changes in the subthalamic nucleus is of particular interest since lesions in this nucleus are known to result in chorea and therefore might contribute to the chorea which is a cardinal symptom of HD.

Novel ERBB4 juxtamembrane splice variants are frequently expressed in childhood medulloblastoma

We recently reported a significant relationship between tumor cell expression of the ERBB4 receptor, the most recently described member of the epidermal growth factor receptor family, and aggressive tumor phenotype in childhood medulloblastoma. Two alternative juxtamembrane (JM) isoforms of the ERBB4 receptor have been described. Termed JMa and JMb, these variants possess different receptor processing and ligand‐binding characteristics. In the current study, we employed an RT‐PCR and sequencing strategy to determine the pattern of ERBB4 JM isoform expression in a large (n = 78) series of pediatric medulloblastomas. JMa and JMb transcript expression was detected in 53% and 28% of tumor samples, respectively. In addition, two novel ERBB4 JM isoforms, which we have termed JMc and JMd, were isolated from 10% and 36% of tumors, respectively. Sequence analysis revealed the JMc transcript to contain a deletion of the entire JM region. In contrast, JMd includes an extended coding region, retaining both the JMa and JMb sequences. Neither of these novel isoforms was detected in normal human adult cerebellum, but expression of JMd was observed in developing fetal cerebellum, suggesting that this later isoform may represent an ERBB4 transcript restricted to primitive neuroectoderm‐derived tissue. To confirm that the four ERBB4 JM isoforms arise by alternative RNA splicing, we sequenced the intron‐exon junctions of the human ERBB4 gene within the JM region. This demonstrated the four ERBB4 JM variants to be encoded by two short exons containing the JMb and JMa sequences positioned in the order 5′ to 3′ and separated by a 121 bp intron.

The growing teratoma syndrome in a nongerminomatous germ cell tumor of the pineal gland

The growing teratoma syndrome is a recognized complication of metastatic nonseminomatous germ cell tumors of the testis and is managed surgically. It may also occur in intracranial nongerminomatous germ cell tumors.