Tumour vascularity is of prognostic significance in adult, but not paediatric astrocytomas

Astrocytomas are the commonest type of brain tumours in adults and children. Although the most reliable prognostic indicators have been shown consistently to be patient age and tumour histological grade, biological progression in these tumours is inevitable and the overall prognosis has remained poor. Due to the evidence that vascular changes are important histological features of astrocytomas, the aim of this study was to investigate prognostic significance of tumour vascularity in paediatric and adult astrocytomas. Study population consisted of 70 patients (45 adult and 25 children) with histologically proven diagnosis of astrocytoma with no history of previous therapy. Histological quantification of tumour vascularity was performed using three different methods: microvessel density, vascular grading and Chalkley counting. Histological classification and grading were also assessed using the World Health Organization system. In contrast to the results in paediatric astrocytomas, tumour vascularity in adult tumours correlated significantly with postoperative survival by univariate analysis (P < 0.05). Microvessel density appeared to be an independent indicator of prognosis by multivariate analysis (P = 0.001). Likewise, patients with microvessel density of 70 or greater had significantly shorter survival than the remaining group (P < 0.001). Patient age and tumour histological grade were also correlated with survival. We conclude that histological quantification of tumour vascularity is a significant prognosticator in adult astrocytomas, but not in children. Our data do not support the validity of applications of antiangiogenic agents in paediatric astrocytic tumours, particularly pilocytic astrocytomas.     

Clinicopathological correlation of cell proliferation, apoptosis and p53 in cerebellar pilocytic astrocytomas

We have analysed 78 cerebellar pilocytic astrocytomas to assess whether histopathology, cell proliferation, apoptosis rate, p53 immunoreactivity, or flow cytometry could predict their long-term behaviour. Classic pilocytic/microcystic pattern was seen in 62 patients and 16 patients had mixed pattern with an additional non-pilocytic glial component. The overall 5-year survival was 93%, complete resection providing 100% survival. The four patients who died during the follow-up were more than 14 years of age, their primary operation had been incomplete and three of them were mixed variants. In 15 cases the tumour recurred giving a recurrence-free 5-year survival of 77%. The proliferation indices were low: Ki-67_MIB-1 (median 2.0%), PCNA (1.2%) and S-phase fraction (4.4%). The Ki-67_MIB-1-labelling index was significantly higher in young patients, but did not differ between the classic and mixed variants. Twenty-two per cent of the tumours were aneuploid with a significantly higher S-phase fraction than in diploid tumours. p53 seems to act as ardian of the genome' in pilocytic astrocytomas, because aberrant/increased expression of p53 and aneuploidy associated with enhanced apoptosis. Only patient age ( P =0.01), radicality of the primary operation ( P =0.0001) and histology (classic vs mixed, P =0.008) significantly correlated with survival. The poorer prognosis of the mixed variant suggests that this may represent a distinct entity. Although none of the novel parameters significantly predicted recurrence or survival, they indicate substantial biological variation among cerebellar pilocytic astrocytomas.     

Epidemiology and prognosis in children treated for intracranial tumours in Denmark 1960–1984

A total of 911 Danish children under 15 years of age were treated for an intracranial tumour in the 25-five year period 1960–1984. All cases were followed up to the end of 1994 or to emigration or death if one of these came sooner. The mean annual incidence was 32.5 per million children with a slight increase over the 25 years. The male/female ratio was 1.15 and close to the M/F ratio for the entire Danish population of children. Of the tumours, 46% were located in the supratentorial and 54% in the infratentorial compartment, and 94% were verified histologically. In order of frequency the most common types were astrocytomas (all grades, 35%), medulloblastomas (20%), ependymomas (14%), and craniopharyngiomas (5%). Total removal of the tumour was performed in 277 and partial removal, including biopsy, in 490 children. In 57 patients a shunt operation only was performed, and 87 children did not have an operation or died before the correct diagnosis was established. Radiotherapy was administered in 55%. The outcome depended on extent of removal, radiation, location and histology of the tumour. Most (784 or 86%) of the children survived more than 1 month after diagnosis or operation, and 353 children (39% of the whole series, 47% of those alive more than 1 month after diagnosis) were alive at follow-up. Of the survivors 29% had a tumour in the supratentorial midline, 26% one in the lateral part of the supratentorial area, 31% a cerebellar tumour and 13% a IV ventricle tumour. It was possible for 66% of the survivors with supratentorial and 90% of those with infratentorial tumours to lead a normal life. The long-term prognosis was especially good for children with cerebellar and supratentorial astrocytomas and optic chiasma tumours. Children with juvenile cerebellar astrocytoma had the best prognosis: 90% were alive at the end of the follow-up period, as against 20% of those with medulloblastoma and 6% of those with glioblastoma. A comparison of the data from the present series and from a similar Danish series of intracranial tumours in 533 children seen in the years 1935–1959 shows no significant differences in location or histology, a slight increase in annual incidence, and improved survival rates during the 50 years in question. Received: 23 February 1998     

Preirradiation ifosfamide,carboplatin, and etoposide (ICE) for the treatment of high-grade astrocytomas in children

Background Astrocytomas are the most common form of primary intracranial tumor; however, survival of patients with high-grade tumors has not changed much compared with that reported in the early 1970s.Objective Our objective was to assess the efficacy, security, and survival rate of postoperative chemotherapy with ifosfamide, carboplatin, and etoposide (ICE) in pediatric patients with anaplastic astrocytomas (AA) and glioblastoma multiforme (GM).Methods In a phase II study, we evaluated 25 children with AA or GM. The proposed treatment was four courses of chemotherapy with ICE followed by hyperfractionated radiotherapy, and then four more courses of ICE. Patients were evaluated using MRI after surgery, after the second course of chemotherapy, and again after the last. Toxicity was determined before each course.Results The overall and disease-free survival at 60 months was 67% and 56% respectively. For supratentorial localization it was 92% at 60 months and 20% at 18 months for brain stem tumors. Fourteen patients had a complete response and 9 died as a result of tumor progression.Conclusions Postoperative chemotherapy with ICE reduces the tumor size and increases the survival rate of pediatric patients with malignant astrocytomas with minimal toxicity.A commentary on this paper is available at     

Supratentorial tumours in infants

Three hundred and ninetysix paediatric (below 15 years of age) patients with brain tumours were treated at our institute in the last 4 years. Eighty-two of the tumours were located supratentorially. These 82 patients included 14 infants (below 1 year of age), who made up 3.5% of all paediatric patients with brain tumours and 17% of those with brain tumours in a supratentorial location. There was a male preponderance, and two-thirds of the 14 patients were within their first 6 months of life. Increasing head size, vomiting and failure to thrive were the common presenting features. One infant presented with asymmetric skull growth. The tumours tended to be large, occupying almost the entire affected cerebral hemisphere; histological types included astrocytomas, malignant astrocytomas, glioblastoma multiforme, primitive neuroectodermal tumours, malignant choroid plexus papillomas and malignant teratomas. Two children had congenital tumours and another two tumours, in children with associated lobar agenesis, were thought to be congenital in origin. Associated hydrocephalus was present in seven patients, but precraniotomy shunt was required in only two patients. The perioperative (within 1 month) mortality was 57%. Only 30% of the patients survived for more than 1 year after surgery and chemotherapy. The longest survival was 20 months. Delay in diagnosis, poor general condition prior to surgery, and the high vascularity and malignant nature of these tumours accounted for the poor results.     

Low grade astrocytomas: controversies in management

Low grade astrocytomas are common brain neoplasms that primarily affect young adults. Although these patients often have a reasonably long survival, most will ultimately succumb to their tumours. Often the tumours progress to higher grade astrocytomas. The optimal management plan for these tumours is controversial and ranges from observation to macroscopic excision, radiotherapy and chemotherapy. The evidence for each of these approaches is presented in this review and a management algorithm is presented.     

Posterior fossa tumors in children with neurofibromatosis type 1 (NF1)

Background

Tumours of the posterior fossa associated with neurofibromatosis type 1 (NF1) are very infrequent. Series studying this association are seldom reported.

Personal experience

In a series of 600 NF1 patients studied during 39 years (1965-2004) only five (0.83%) had posterior fossa tumours. They were studied clinically, radiologically by computerized tomography (CT) or magnetic resonance (MR) and histologically. Four of them had astrocytomas but only in one case was the tumour primarily cerebellar while the tumour was primarily of the brain stem with invasion of the adjacent regions of one or both cerebellar hemispheres in three patients. The fifth tumour was a medulloblastoma that had a survival of 3 years following treatment. The patient with primary cerebellar astrocytoma is apparently cured 7 years after the removal of the tumour. The patients with the brain stem tumours extending to the cerebellum, showed a chronic slowly progressive cerebellar disease, but remain alive at age of more than 20 years (one was lost to follow-up).

Discussion and conclusion

The aim of this study was to present five children (one male and four females) less than 16 years of age when they were initially seen in our service, who had NF1 associates with posterior fossa tumours. This location is very uncommon in patients with NF1, in contrast with those located in other regions, such as pathway optic tumours and brain stem tumours. Most of these tumours are histologically benign (low grade astrocytomas). Only one patient in this series had a medulloblastoma, an exceptionally rare tumour seldom reported in patients with NF1.     

Spinal cord astrocytomas: long-term results comparing treatments in children

Technology enabling radical resection has expanded treatment options for children with spinal cord astrocytomas. Comparison of long-term survival and neurological function after complete tumor removal with more conservative treatment may determine whether radical surgery can improve outcome in well-differentiated and anaplastic spinal cord astrocytomas. In all, 18 children with spinal cord astrocytomas were initially treated between 1976 and 1992 with biopsy in 6, subtotal removal in 7, and complete resection in 5. Seven had anaplastic tumors. Nine children treated before 1988 received radiotherapy. Survival after a median follow-up of 11 years was 82% (9/11). Five patients with anaplastic tumors are alive between 12 and 18 years after treatment. No patient relapsed after total resection, whereas more than two-thirds treated with other than complete resection relapsed within 3 years (P=0.029). All but 1 patient with symptomatic relapse received radiotherapy (P=0.059). Magnetic resonance imaging more than 3 years postoperatively showed no recurrences in 13 of the 15 survivors and asymptomatic progression in the other 2. Although excellent long-term survival was seen, frequent relapse was associated with either incomplete resection or radiotherapy. Prolonged relapse-free survival was observed in all patients treated with complete resection, including 3 with anaplastic tumors. Received: 31 January 1997     

Long-term follow-up after surgical treatment of cerebellar astrocytomas in 100 children

A retrospective study was performed in 100 children, who were operated on between 1954 and 1984 for cerebellar astrocytoma. Twenty-nine patients died during the 1st month after the operation. Of the patients who survived, 24 lived up to 5 years, 17 up to 10 years, and 30 lived 20 or more years. In 22 cases, tumor recurrence was the reason for reoperation. Radiation therapy was used in 25 cases with histological malignancy and/or after partial removal of the tumor. The analysis in 6 cases with brainstem involvement allowed us to conclude that in such cases the prognosis is poor with regard to survival. Although total removal of cerebral astrocytomas appears to be the most effective form of treatment, we are of the opinion that even subtotal excision may be compatible with long-term survival. This suggests that many of these tumors may show benign biological behavior.Presented at the XIth Meeting of the European Society for Pediatric Neurosurgery, Naples, 1988     

Childhood medulloblastoma in Denmark 1960–1984 A population-based retrospective study

Medulloblastoma is a common paediatric brain tumour, located in the cerebellum and in the IV ventricle, surpassed in frequency only by astrocytomas. 180 children below the age of 15 with a medulloblastoma of the posterior fossa were treated in Denmark in the 25-year period from 1960 to 1984 and followed up until the end of 1996, or until death. During the 25 years they accounted for 20% of all intracranial tumours in children in Denmark. All tumours were histologically verified. The mean annual incidence was 6.4×10^–6, decreasing slightly with a factor of 0.12×10^–6 per year. The male/female ratio was 2.1 – twice that of the background population of children (1.05). The 5-year survival rate following diagnosis, surgery and radiotherapy was 23%, and the 25-year survival rate was 16%. The 5-year survival rate was 8% in the first 5-year period of 1960–1964, increasing to 36% in the last period 1980–1984. Presumably the increase in survival depends on many factors, e.g. improved diagnostic methods and neuroanaesthesia, better operative technique (microscope), improvements in radiotherapy and the introduction of chemotherapy. The best predictive factors of a good prognosis were preoperative CSF shunting, radical tumour removal and complete radiotherapy, i.e. irradiation of the brain, tumour bed and spinal cord. The survival rate in the last five-year period was seven times higher than the survival rate found in a comparable Danish study from the years 1935–1959. Most of the children followed Collins law of risk index. The results of treatment in children with medulloblastoma remain unsatisfactory. Accordingly, participation in international prospective studies of multimodal treatment should be encouraged, possibly using chemotherapy prior to surgery.     

Has modern management improved the outcome of infants with intracranial tumours?

Records of 92 children were reviewed who, in the first 18 months of life had an intracranial tumour, and who were registered with the Manchester Children's Tumour Registry during the 34-year period from 1953 to 1987. The incidence of intracranial tumour was 1 in 25000 live births, and 85% of the tumours were malignant. The introduction of computed tomography (CT) in the region in 1976 improved the diagnostic accuracy and led to early diagnosis. This also coincided with refined radiotherapy and improved chemotherapy. The surgical attitude became more aggressive, and with early treatment, mortality was reduced, though the 1-month operative mortality still remains high at 15%. All survivors were available for follow-up. All children with axial tumours died within 9 years. Long-term follow-up did not suggest significant improvement in the overall survival or in the quality of life, though there was a significant improvement in the 5-year survival rate with modern management.     

儿童与成人脑干星形细胞瘤临床特点及手术疗效比较

目的比较病理级别相同的儿童和成人脑干星形细胞瘤病人的临床特点和手术疗效的差异。方法回顾性分析40例病理级别相同(WHO分级Ⅱ级)的脑干星形细胞瘤病人的临床资料,包括儿童组10例,成人组30例。比较两组的一般资料和手术疗效差异,并采用Kaplan-Meier法分析两组术后1年生存率。结果肿瘤侵犯脑神经数目,在儿童组和成人组组间的差异具有统计学意义(P=0.017);病人性别、MRI显示肿瘤有无强化、肿瘤部位、大小、切除程度,入院时的日常生活质量评分(KPS)及出现症状至手术时间等方面,两组间差异均无统计学意义。生存分析显示:儿童组平均生存16.5个月,术后1年生存率为55.6%,成人组平均生存35.2个月,术后1年生存率为83.3%;成人组脑干星形细胞瘤预后优于儿童组(P=0.005)。结论病理级别相同的成人和儿童脑干星形细胞瘤,成人预后好于儿童;与成人比较,儿童脑干星形细胞瘤浸润生长明显。     

Prognostic implications of microvessel morphometry in diffuse astrocytic neoplasms

Astrocytic brain tumours, particularly malignant astrocytomas, are recognized to be highly vascular neoplasms with potent angiogenic activity. Recent research has shown that quantification of microvessel density (MVD), as a measure of the degree of angiogenesis, constitutes a strong prognostic indicator in patients with astrocytomas. However, the significance of other morphometric aspects of microvessel network has not been tested so far. In this report, histological sections from 70 astrocytomas (grades II to IV), immunostained for CD34, were evaluated by image analysis for the quantification of MVD, total vascular area (TVA), and microvascular branching, as well as several morphometric parameters related to vessel size or shape. Minor axis length increased with grade (P = 0.045) but MVD and TVA presented a peak in grade III (P = 0.033 and P < 0.001, respectively). Size and shape related parameters affected survival in univariate analysis of grade IV and grades II/III, respectively. In multivariate analysis, only branching counts, along with age and grade, were the independent predictors of survival. Although MVD, TVA and branching counts were adversely related to disease-free survival in grades II and III (univariate analysis), only TVA remained statistically significant in multivariate analysis. It is concluded that TVA and branching counts are prognostically more informative than MVD for patients with diffuse astrocytic tumours.     

Tumours of the third ventricle in children

Experience with 25 cases of tumour of the third ventricle in children is reviewed. The majority of the lesions were infiltrating astrocytomas of the anterior and mid-portions of the third ventricle. These tumours were generally inoperable. However, other tumours within the third ventricle were benign, encapsulated, and resectable. Surgical exposure was carried out through one of three routes: posterior fossa, transcallosal, or subfrontal. The radiological criteria by which the operative approach is determined are discussed.     

Low-grade supratentorial astrocytomas in adults: Management, immunohistochemical analysis and long-term follow-up

A retrospective review of supratentorial, low-grade astrocytomas in adults over a 10-year period (1983-1993) was performed. All 62 patients had computed tomography and surgery with histological and immunohistochemical analysis of the tumour. Radiotherapy was administered to all patients, regardless of the extent of surgical resection. Multivariate analysis showed that age of the patient at the time of surgery (P=0.008) and female sex (P=0.031) were the most important indicators of improved survival. No significant survival advantage was found with any particular symptom or symptom duration. Neither presence of a tumour cyst nor site of the tumour affected survival. Histological grading (St Anne-Mayo system) found 61 grade II astrocytomas (98%) and one grade I tumour. Six tumours (10%) were protoplasmic astrocytomas and 56 cases (90%) were diffuse fibrillary astrocytomas. Proliferation index derived from Ki-67 antibody staining and the presence of p53 protein expression were not significantly correlated with survival. Most patients underwent biopsy (79%) with 8% undergoing subtotal and 13% total resection. Increased extent of surgical removal showed a trend towards an improved survival (P=0.05). No survival advantage was found with increasing radiotherapy dose. Median survival in the study population was 5.1 years, with survival rates of 70% at 2 years and 53% at 5 years. The follow-up period ranged from 1 to 10.5 years. Younger age, female sex and the extent of surgical resection are important prognostic factors in the management of low-grade astrocytomas, whereas the efficacy of postoperative radiotherapy needs further evaluation. The prognostic significance of Ki-67 and p53 expression in low-grade astrocytomas remains to be determined.     

Sub-classification of low-grade cerebellar astrocytoma: is it clinically meaningful?

OBJECTIVES: The objectives were to identify prognostic factors for the survival of children with cerebellar astrocytoma, and to evaluate the reproducibility and prognostic value of histological sub-classification and grading. METHODS: Children aged 0-14 years treated in Denmark for a cerebellar astrocytoma in the period 1960-1984 were included and followed until January 2001 or until their death. The histological specimens from each patient were reviewed for revised grading and classification according to three different classification schemes: the WHO, the Kernohan and the Daumas-Duport grading systems. RESULTS: The overall survival rate was 81% after a follow-up time of 15-40 years. The significant positive prognostic factors for survival were "surgically gross-total removal" of the tumour at surgery and location of the tumour in the cerebellum proper as opposed to location in the fourth ventricle. No difference in survival time was demonstrated when we compared pilocytic astrocytoma and fibrillary astrocytoma. Moreover, we found that the Kernohan and the WHO classification systems had no predictive value and that the Daumas-Duport system is unsuitable as a prognostic tool for low-grade posterior fossa astrocytomas. CONCLUSION: Discordant observations due to interobserver variability make histological sub-classification of low-grade cerebellar astrocytomas in children insufficient for predicting prognosis and biological behaviour. Similar survival rates in a population of paediatric low-grade cerebellar astrocytomas of grades I and II indicate that tumour grade has no prognostic significance within this group of patients. "Surgically gross-total removal", especially if the tumour is located in the fourth ventricle is of the highest importance for long-term survival. Histological sub-classification of the tumours has no predictive value.     

Paediatric brain tumours treated at a single,tertiary paediatric neurosurgical referral centre from 1999 to 2010 in Australia

Paediatric brain tumours are the most common solid tumour of childhood and the most common cancer cause of death among children. A retrospective review of 313 histopathologically proven brain tumours over an 11-year period has been performed at the Children’s Hospital Westmead, New South Wales, Australia, to determine proportions and locations of different tumours, age distribution, survival rates and usage of various treatment modalities. Pilocytic astrocytoma was the most common paediatric brain tumour (29%) followed by medulloblastoma (12%) and ependymoma (6%). Most tumours were histologically benign (59%), and 42% of tumours were located in the posterior fossa. The average age at diagnosis was 7.9 years. About 50% of children were treated with surgery alone, whereas the other 50% had surgery or biopsy plus adjuvant treatment. The overall one-year survival rate was 89% and the five-year survival rate was 80%. The five-year survival rates for pilocytic astrocytoma was 91%; medulloblastoma, 75%; ependymoma, 82%; and high grade glioma, 15%. Thus, a large proportion of paediatric brain tumours were histologically benign and were treated with surgery alone, but a subset of benign tumours required adjuvant treatment and were associated with mortality (25%). The overall survival rates were high and are improving, although for some tumours, such as high grade glioma, the outlook remains poor.     

Reproductive factors have low impact on the risk of different primary brain tumours in offspring

OBJECTIVES: The aim of our study was to investigate whether reproductive factors influence the risk of primary brain tumours (PBT) in offspring. METHODS: Data on all deliveries in two Swedish counties from 1955 to 1990 were extracted from two birth registries. The follow-up period closed at the end of 1994, with subjects followed up to early middle age. Incidence rates of malignancy for 1958-1994 were obtained from the Swedish Cancer Registry. Standardised incidence ratios (SIR) and relative risks were calculated for astrocytomas, primitive neuroectodermal tumour, ependymoma and meningiomas in offspring. RESULTS: Few associations were detected. High birth weight indicated an increased risk for astrocytomas grade I and II for all primary brain tumours, and the risk was close to significance for astrocytomas grade I-II (SIR = 3.64; CI = 0.98-9.31). For children under 15 years of age the risk for astrocytomas grade I and II was further increased (SIR = 4.44; CI = 1.19-11.38). CONCLUSIONS: A consistent pattern of non-association indicated a low impact of intrauterine environment on the future development of primary brain tumours in offspring up to early middle age.     

Suprasellar pilocytic astrocytoma: one national centre’s experience

Introduction

Pilocytic astrocytomas in the supratentorial compartment make up 20 % of all brain tumours in children with only 5 % of these arising in the suprasellar region. Optic pathway gliomas or suprasellar gliomas are often seen in neurofibromatosis type 1 (NF1) patients. Given their location, suprasellar pilocytic astrocytomas are challenging to manage surgically with high morbidity rates from surgical resection. We assess our cohort of patients with suprasellar pilocytic astrocytoma and document our experience.

Method

A retrospective review of patients diagnosed with suprasellar glioma between 2000–October 2012. We included patients diagnosed with optic pathway glioma based on radiological features (with or without biopsy) and those who had a biopsy confirming pilocytic astrocytoma.

Results

Fifty-three patients included (sporadic tumours 24 and NF1 related 29). Fifteen sporadic and four NF1 patients were biopsied. Twelve sporadic and 13 NF1 patients were initially treated with chemotherapy while only 1 patient had radiotherapy initially. Progression was noted in 58 % of the sporadic group and 24 % of the NF1 group. The only significant factor for progression was NF1 status (p?=?0.026).

Conclusion

Management should be guided by individual patient circumstance. In our cohort, chemotherapy did not significantly improve progression free survival; however, NF1 status significantly correlated with the decreased progression.