Fifty years of paediatric malignant bone tumours in the West Midlands, UK, 1957-2006: incidence, treatment and outcome.

Malignant bone tumours in the paediatric age group (0-14 years) are uncommon; various aetiological theories exist and few reports of incidence, age and sex distributions have been published. We examined the incidence of childhood malignant bone tumours in one large single region of the UK over an extended period of 50 years. The West Midlands specialist regional children's tumour registry holds data on all malignancies and benign brain tumours in children under 15 years in the West Midlands region, which has a population of around 1 million children. Demographic and clinical data have been abstracted and diagnoses reviewed by a panel of expert pathologists. During the period 1957-2006, 259 cases of malignant paediatric bone tumours were diagnosed. There were 153 osteosarcomas, 78 Ewing sarcomas and 28 other primary bone tumours. The overall age standardised rate was 4.66, with no increase over time, although there was a significant increase in the incidence of Ewing sarcomas in the period 1965-92. Sixty-eight per cent of tumours were in patients over 10 years, whereas the incidence in patients under 10 years showed a non-significant increase. Survival rates increased dramatically post-chemotherapy introduction, with Ewing sarcoma demonstrating better survival overall. This is a large study giving an overview of malignant bone tumours in the childhood population of a single region over an extended period, showing results consistent with national reports. It also examines late effects, which were mostly mobility/orthopaedic, although almost one-fifth of patients had cardiac problems and five went on to develop second malignancies.

Congenital abnormalities and clinical features associated with Wilms' tumour: a comprehensive study from a centre serving a large population.

Altogether 156 children treated for Wilms' tumour (WT) between 1970 and 1998 were studied. Sixty-six children, selected only by their attendance at clinic, were carefully examined and the findings compared to those from a case note review of 90 children. Congenital abnormalities were present in 45% of the examined cohort, in 19% of the case notes review group and in 30% overall. Novel findings included the association of WT with Marshall Smith syndrome, developmental delay in 3 of 4 cases of WT (one bilateral) and 1 sibling from consanguineous Pakistani families and another sibling also had leukaemia. The possibility of rare DNA repair or cancer predisposing disorders among these 4 families requires further study. Careful examination and history taking of an unselected patient cohort revealed a higher than expected incidence of clinical abnormalities which may be overlooked if not specifically sought.

Caring for survivors of childhood cancers: the size of the problem.

Many survivors of childhood cancer have significant health problems due to their illness or treatment. This population-based study examines the number of long-term survivors, their disabilities and consequent long-term care needs. Survival rates for children diagnosed with cancer between 1960 and 1999 in the West Midlands, United Kingdom (UK), were used to estimate future long-term survivor numbers. Treatment and late effects data on a cohort of patients surviving for more than 5 years were used to consider continuing care needs. Between the 1960s and 1990s, 5-year survival increased from 23% to 70%. There were 98 5-year survivors in 1970, and numbers may exceed 2,100 by the end of 2005. Most (at least 61%) survivors in the West Midlands Region have one or more chronic medical problems and may require multidisciplinary care. We conclude that, in order to determine how to provide cost-effective care for this increasing population, protocol delivered management with audit is needed.

'Clustering'--real or apparent? Probability maps of childhood cancer in the West Midlands Health Authority region.

The West Midlands Regional Children's Tumour Registry collects detailed information on all cases of childhood cancer in the West Midlands Health Authority Region (WMHAR). The distribution by electoral ward of all cases diagnosed in the WMHAR between 1980 and 1984 has been determined. Analysis has also been performed for leukaemias/non-Hodgkin's lymphomas alone. We suggest that this latter grouping should be universally employed, owing to the difficulty of accurately separating out cases of leukaemia. Both spatial analyses showed several wards with significantly excessive rates on the basis of their cumulative Poison probability. Observed/expected ratios of 3-35 were seen for cases in significant wards, which are similar to the ratios seen in analysis of incidence around nuclear installations. However, further detailed consideration of these individual significance levels in the light of the number of statistically significant wards which would occur by chance alone, due to the multiple use of the test, accounted completely for the number of wards obtained in each of the groups considered. Thus, apparent 'clustering' of cases could be mere statistical artefact. In the WMHAR, therefore, using the technique of probability mapping, no true spatial pattern of incidence was found, other than that which would occur by chance alone. This, in a large area without nuclear installations and an even mix of rural and industrialised regions, could be seen as control data for those studies which have considered cases of childhood leukaemia around nuclear facilities, where the observation of single point clusters associated with suspected sites restricts assessments of spatial pattern in the rest of the area.(ABSTRACT TRUNCATED AT 250 WORDS)

Retrospective study of prognostic value of DNA ploidy and proliferative activity in neuroblastoma.

AIM: To assess the prognostic value of age and stage at diagnosis, site of primary tumour, cell ploidy and N-myc copy number in children with neuroblastoma. METHODS: Flow cytometry was used to determine the cellular DNA content of paraffin wax embedded archival material from 69 cases of neuroblastoma and was successful in 52. RESULTS: The age, stage, and survival distribution of the sampled cases was not significantly different from that in a larger population based series. There were seven diploid ("non-aneuploid") and 45 aneuploid (including two tetraploid and four triploid) tumours. The 10 year survival was significantly better for cases of aneuploid rather than diploid tumours (p < 0.05). An important new finding was that 10 year survival was also significantly better for tumours with a low percentage of cells in S phase (p < 0.03). CONCLUSION: The percentage of cells in S phase, a measure of the proliferative activity of the tumour, correlated with prognosis in neuroblastoma. This should be measured with other biological features of the disease, such as N-myc copy number, when prognostic indicators are being assessed.

Congenital mesoblastic nephroma: possible prognostic and management value of assessing DNA content.

The case records and pathology of all children with kidney tumours treated in the West Midlands Health Authority Region (WMHAR) from 1957 to 1986 were reviewed. The histology was reviewed by a panel of three paediatric pathologists. Thirteen (6%) out of 211 cases were considered to have congenital mesoblastic nephroma (CMN). Nine were of the conventional type, three of the atypical cellular type, and one mixed. DNA ploidy was investigated and showed two of the tumours to be aneuploid and nine diploid (tissue was not available in the two other cases). The two aneuploid tumours were of atypical cellular and mixed histology, respectively; the diploid tumours were of the conventional type in eight cases and atypical cellular in one. The atypical cellular type has been reported to behave more aggressively, but the benefit of additional treatment after surgery to prevent recurrence remains unclear. Measurement of DNA content by flow cytometry, together with histological subclassification, may be useful in selecting patients who will benefit from further treatment after surgery.

Immunophenotypic analysis of childhood Burkitt's lymphoma in the West Midlands 1957-1986.

AIMS: To analyse the immunophenotype of a large number of non-endemic Burkitt's lymphomas to determine whether a B cell phenotype is consistently recognisable using formalin fixed, paraffin wax embedded archival material and a standard panel of commercially available antibodies. METHODS: Archival material was obtained from 30 cases of childhood Burkitt's lymphoma registered with the West Midlands Regional Children's Tumour Research Group. These were analysed by a standard avidin biotin complex immunoperoxidase method using antibodies to CD45, CD43, CD30, CD20, CD15, and immunoglobulin heavy and light chains. RESULTS: There was a high incidence of the CD45RB and CD20 immunophenotypes, with a clearly recognisable B cell lineage even in archival material. IgM was identifiable in 13 of the 23 (56.5%) cases tested. Only three of 17 (18%) cases expressed CD30. Positive membrane staining with CD45RO was observed in two (6.7%) cases. CONCLUSIONS: A B cell lineage can be identified in Burkitt's lymphoma in formalin fixed, paraffin wax embedded material, even in archival tissue. There was a low incidence of membrane staining with CD45RO which is a potential source of diagnostic confusion.

Childhood cancer in the West Midlands: incidence and survival, 1980-1984, in a multi-ethnic population.

The purpose of this study is to describe the incidence and survival of childhood cancer in the West Midlands for the period 1980-1984. Proportional breakdown by Asian subgroup is also considered. A total of 587 patients were registered, 49 of them of Asian origin. Breakdown to Asian versus non-Asian subgroups by diagnosis revealed comparatively high rates for Hodgkin's disease, retinoblastoma and neuroblastoma in the Asian patients. However, a deficit of cases was seen for CNS tumours. Comparison of overall age-standardized rates (ASR) for all cancers revealed a substantially lower value compared to that reported for the USA white population but a similar value to the USA black and UK white populations. Diagnostic breakdown revealed that the major difference between the West Midlands Regional Children's Tumour Research Group (WMRCTRG) and the USA white ASR was in the leukaemia and lymphoma group. Overall survival for the series was 56% at 5 years. The poorest prognosis was found in acute myeloid leukaemia, with only 23% of patients surviving at 5 years, against 62% in acute lymphoblastic leukaemia. CNS tumours also had a poor outcome, with an overall survival rate of 47%, although certain individual diagnoses were more favourable. We observed a 100% survival rate in Hodgkin's disease up to 5 years from diagnosis, and both Wilms' tumour and retinoblastoma had 90% survival rates.

Descriptive epidemiology of primary central nervous system tumours in children: a population-based study.

This study was undertaken to investigate the incidence, outcome and referral patterns of central nervous system tumours in a defined childhood population over a recent 5-year period. The study incorporated pathological review of all available diagnostic material and follow-up assessed survival at a minimum of 5 years from diagnosis. One hundred and forty-seven cases were reviewed, representing an annual incidence of 26.5 per million children aged less than 15 years. The distribution of individual diagnoses by age, sex and anatomical site was similar to comparable data collected previously in the United Kingdom and North America, but the inclusion of 28 cases (19%) without biopsy suggested that the wider use of computed tomography might account for a small increase in incidence over previous estimates. Analysis of referral to the Regional Paediatric Oncology Unit showed that the patients referred were younger than those not referred and were over-represented amongst the diagnoses of medulloblastoma, ependymoma and brain stem glioma, which carry the worst prognosis. Survival for all diagnoses together was 51% at 5 years, ranging from 13% for unbiopsied brain stem gliomas to 100% for juvenile astrocytomas. Referral to the Regional Unit appeared to have some survival advantage for children with medulloblastoma, although this was not statistically significant. Accurately reviewed data such as these are essential in order to assess current workload and treatment success, in addition to enabling investigation of future diagnostic and treatment strategies.

Paraganglioma of the vagina: the first report of a rare tumor in a child.

Paraganglioma (extra-adrenal pheochromocytoma) is a rare tumor, particularly in childhood. Those in the female genital tract are exceptionally rare, with only 9 cases reported in detail since 1926. All were seen in adults and only two arose in the vagina. This study examined the incidence of this tumor in the childhood population of the West Midlands region of the United Kingdom since 1957 and found 4 cases: 2 abdominal, 1 para-aortic, and 1 carotid body. A recent additional case is reported in the vagina of a child aged 11 years, who presented with heavy vaginal bleeding in the absence of hypertension. Initial diagnosis suggested rhabdomyosarcoma and near complete excision was carried out. Since this is the first such case to be described in a child, the outcome can only be assumed. Although histopathological examination suggested the benign nature of the tumor, implying that surgical excision was sufficient treatment, close follow-up is recommended.

Is the risk of cancer increased in Asians living in the UK?

The pattern of cancer in white and Asian (Indian, Pakistani, and Bangladeshi) children living in the West Midlands Health Authority Region was investigated using age standardised incidence rates. Two sets of rates were calculated, a 10 year rate (1982-91) using survey based estimates of the ethnic population and a four year rate (1989-92) using the ethnic population counts from the 1991 census. The 10 year rates showed a significantly higher annual incidence of cancer in Asian (159.1/million/year) than in white (130.8) children. The pattern of cancers in Asian children was different, with an excess of lymphomas and germ cell tumours, and a deficit of rhabdomyosarcomas. These findings were confirmed by the four year rates. Although underestimation of the Asian population probably contributes to the apparent excess, there remains cause for concern that UK Asian children may be at higher risk of cancer. Accurate ethnic population figures and confirmatory studies are urgently required.

Factors affecting survival in White and Asian children with acute lymphoblastic leukaemia.

Some studies suggest that Asian children with leukaemia have a worse outcome than Whites. Survival of Asians with ALL treated at the Birmingham Children's Hospital from 1975 to 1994 was the same as that of Whites, despite their greater deprivation and poorer nutrition. For one 5-year period (1980-1984) Asians had significantly poorer survival, even after adjustment for prognostic factors. Poor treatment compliance during that period may have contributed to this difference.

Hodgkin's disease in children in the West Midlands, 1957-1986: a large population-based study.

One hundred forty-one children were diagnosed with Hodgkin's disease between 1957 and 1986 in the West Midlands Health Authority Region (1991 population, 1.1 million children). Eighty-seven were boys and 54 were girls, representing a significant male:female ratio of 1.5:1 (P < 0.01). The average age-standardized incidence rate was 3.6 per million per year with a significant increase in the older age group (> or = 10 years) in the second half of the period (P = 0.02). The mixed cellularity subtype was more common in those younger than 10 years, with nodular sclerosing disease being seen more in those < or = 10 years. Overall survival at 5 years was 76% (65% at 10 years) with a significant difference (P < 0.001) in survival between the first and last decades. There was six second malignancies, five of which could have been treatment related. A positive history of cancer in close relatives was found in 11 patients, and higher social class was found in more older than younger children. These findings support the hypothesis that Hodgkin's disease may have a viral etiology and may be linked with socioeconomic conditions.

Cancer and congenital abnormalities in Asian children: a population-based study from the West Midlands.

Cancer and associated congenital abnormalities were investigated in Muslim and non-Muslim Asian children from the West Midlands. Cancer incidence rates were calculated for Indian (non-Muslim), Pakistani/Bangladeshi (Muslim) and white children diagnosed from 1978 to 1992. Incidence was significantly higher in the Pakistanis, with an age-standardised rate (ASR) of 163 cases per million per year, compared with 115 for Indian and 125 for white children. Among Asian cancer patients, congenital malformations were significantly more common in Muslim (21%) compared with non-Muslim (7%). In Muslims the malformation excess was caused by autosomal recessive and dominant disorders (in 8% and 5% of cases respectively). Cancer malformation/predisposition syndromes were found in 10% of Muslims, compared with 2% of non-Muslims. In 33% of the Muslims with malformations, childhood cancer and a malformation were also present in a close relative. None of the non-Muslims with malformations had a relative with childhood cancer. The cancer excess in Muslims may be partly related to inherited genes causing both malformations and cancer. The prevalence of autosomal recessive disorders may be related to consanguinity, which is common in the Pakistani Muslim population. The high incidence of autosomal dominant disorders may be related to older paternal age at conception, giving rise to spontaneous mutations.

Thirty years of retinoblastoma (1960-89): changing patterns of incidence.

This study of a 30-year population-based dataset investigates further an earlier observation that the incidence of sporadic bilateral retinoblastoma appeared to be increasing in recent years in the West Midlands Health Authority Region (WMHAR). Stringent measures were applied to ensure complete ascertainment of all cases of retinoblastoma in children in the region, resulting in a total of 117 cases diagnosed during the period 1960-89 in the WMHAR. Hospital case notes were abstracted and follow-up data obtained. Incidence rates were calculated. The overall incidence remained constant over the 30-year period, but that of sporadic bilateral tumours increased, with a corresponding decline in familial cases. There was a statistically significant excess seen in Asian children.

Changing incidence and geographical distribution of malignant paediatric germ cell tumours in the West Midlands Health Authority region, 1957-92.

The West Midlands Regional Children's Tumour Research Group holds high-quality data from 1957 on all childhood cancers in the West Midlands Health Authority region. Since it has been reported that malignant germ cell tumours are increasing in incidence in the north-west of England, we undertook to examine rates in this region and to map the distribution of cases in order to assess any geographical changes in incidence rates. We identified a total of 102 malignant germ cell tumours (MGCTs) between 1957 and 1992. The average age-standardised rate was 1.6 per million per year in the period 1957-74 and 3.6 per million per year during 1975-92, a significant increase (P = 0.0004). Particular increases were noted in older children (10-14 years); P = 0.0002) and in yolk sac (endodermal sinus) tumours (P = 0.004). A small excess was also observed in Asian children when compared with other diagnoses. Geographical analysis showed particularly higher rates at health district level in the West Midlands conurbation as compared with the other areas in the period 1975-92. These factors suggest the possibility that industrial/urban or population effects may be implicated in the observed increase in childhood MGCT and we recommend these areas for further studies.

Trilateral retinoblastoma. A report of five patients.

BACKGROUND: Trilateral retinoblastoma is a well recognized, although rare, syndrome. Most of the reported cases have involved a family history of retinoblastoma (RB) and the disease is almost always fatal. The authors chose to investigate the cases of trilateral retinoblastoma occurring in the West Midlands, a region of the United Kingdom with an increasing incidence of bilateral sporadic RB. METHODS: Five patients with trilateral retinoblastoma (including two were previously reported), diagnosed in 146 consecutive patients with RB in the West Midlands Health Authority Region between 1957 and 1994, are presented (an incidence of 3%). Their clinical presentation, treatment, and outcome are described. RESULTS: There were 4 patients with pineoblastoma, only one of whom had a positive family history. The mean age at diagnosis of RB and 6 months, whereas the patients with pineoblastoma were diagnosed at a mean age of 2 years 8 months. The tumors were not evident on the initial computed tomography scans. One child presented with a calcified suprasellar mass 13 months before the bilateral sporadic RB was identified. Death occurred within 1 month of diagnosis of the intracranial tumor in 3 patients who did not receive any treatment. In the other 2 patients who were treated, death occurred at 15 months and 2 years 7 months, respectively, after diagnosis of intracranial tumor. CONCLUSIONS: Early diagnosis with regular neuro-imaging and more aggressive treatment may improve prognosis in patients with RB and an intracranial tumor.

Neonatal tumours: a thirty-year population-based study.

Estimates of the incidence and outcome of tumours in neonates are uncertain and most reports relate to selected experience in single centres. The definition of neonatal tumour is also unclear and histology is not always an accurate predictor of outcome. This report documents the incidence, clinical features, and outcome of neonatal tumours (birth-3 months) in a population-based paediatric register over a 30-year period from 1960-89. Case note and pathology review identified 170 cases for analysis, of which 21 were leukaemias, 14 CNS tumours, and 135 solid tumours of differing types. Fifty-eight percent were diagnosed in the first month and mature teratoma was the most common diagnosis (29%). Overall incidence increased over the period of the study. Important family medical history was identified in 16% of cases and 15% of patients had associated congenital abnormalities. Overall survival at 1 year was 55%, with leukaemia having the poorest prognosis. Treatment strategies must be individualised but many patients may have a better prognosis than expected and would benefit from assessment at a designated paediatric oncology centre.

Carcinoid tumours of the appendix in children 1957-1986: incidence, treatment and outcome.

Forty carcinoid tumours of the appendix were identified in children under 15 years of age between 1957 and 1986 from the records of the West Midlands Regional Children's Tumour Research Group. A significant excess of girls was observed (P = 0.02). All tumours were discovered incidentally and two patients underwent further surgery. Twenty-two of the 29 confirmed locations (76 per cent) were at the tip of the appendix and 34 of the 40 tumours (85 per cent) had invaded beyond the appendiceal submucosa. The reported incidence rate of 1.14 per million children per year remained constant throughout the study period. No recurrences, metastases or deaths from tumour were detected. Appendicectomy alone is confirmed as usually curative, although right hemicolectomy is occasionally necessary. Caution during routine appendicectomy is recommended to avoid possible tumour damage, as is consistent histological examination of all appendices in the paediatric age group. The importance of long-term follow-up is emphasized.

Thirty-year population-based review of childhood renal tumours with an assessment of prognostic features including tumour DNA characteristics.

We have reviewed all paediatric kidney tumours seen in the West Midlands Health Authority Region over a 30-year period. There were 205 cases confirmed after a review of the pathology by three paediatric pathologists. Seven were cases of bone metastasising renal tumour (clear cell sarcoma), 5 were rhabdoid tumours, 2 were renal cell carcinomas, and 13 were mesoblastic nephromas. In 3 cases, it was not possible to define further the histological diagnosis. The remaining 175 cases were considered to be Wilms' tumour (86%), which is equivalent to an incidence of 5.7/10(6)/year. In the cases of Wilms' tumour, there were 91 boys and 84 girls (1.1:1). The majority of patients were Caucasian with only 7% of non-Caucasian origin. At presentation, 78% of the patients were less than 5 years old. All of these patients except 9 had surgery as part of their treatment, 154 children had total nephrectomy, 3 had partial nephrectomy, and 9 had other surgical procedures. The majority also received chemotherapy and radiotherapy. Sex, chemotherapy, and stage all had prognostic significance in univariate analysis. The actuarial survival at 10 years increased from 17% for patients treated in the first decade of the study to 78% for patients treated in the third. DNA characteristics were investigated using flow cytometry in paraffin-embedded material and adequate information was obtained in 73 cases of Wilms' tumour. Only 7 had aneuploid tumours. Univariate survival analysis of these 73 results showed that stage, sex, the percentage of cells in the synthetic phase and the proliferative index from the DNA investigations had predictive value.